KR102470709B1 - Anti-cd3 antibodies, bispecific antigen-binding molecules that bind cd3 and cd20, and uses thereof - Google Patents

Abstract

The present invention provides antibodies that bind to CD3 and methods of using the same. According to certain embodiments, an antibody of the invention binds with high affinity to human CD3 and induces human T cell proliferation. The present invention includes antibodies that bind to CD3 and induce T cell-mediated killing of tumor cells. According to certain embodiments, the present invention provides a bispecific antigen-binding molecule comprising a first antigen-binding domain that specifically binds human CD3, and a second antigen-binding molecule that specifically binds human CD20. to provide. In certain embodiments, the bispecific antigen-binding molecules of the invention are capable of inhibiting the growth of B-cell tumors expressing CD20. Antibodies and bispecific antigen-binding molecules of the present invention are useful for the treatment of diseases and disorders in which an upregulated or induced targeted immune response is desirable and/or therapeutically beneficial. For example, the antibodies of the present invention are useful for the treatment of various cancers and other CD20-related diseases and disorders.

Description

ANTI-CD3 ANTIBODIES, BISPECIFIC ANTIGEN-BINDING MOLECULES THAT BIND CD3 AND CD20, AND USES THEREOF}

The present invention relates to antibodies, and antigen-binding fragments thereof, specific for CD3, and methods of use thereof. The invention also relates to bispecific antigen-binding molecules that bind CD3 and target molecules, such as CD20, and methods of their use.

CD3 is a homodimeric or heterodimeric antigen expressed on T cells in association with the T cell receptor complex (TCR) and is required for T cell activation. Functional CD3 is formed from the dimeric association of two of four different chains: epsilon, zeta, delta and gamma. CD3 dimeric configurations include gamma/epsilon, delta/epsilon and zeta/zeta. Antibodies to CD3 have been shown to cause T cell activation in a manner similar to engagement of the TCR by peptide-loaded MHC molecules by clustering CD3 on T cells. Accordingly, anti-CD3 antibodies have been proposed for therapeutic purposes involving the activation of T cells. Bispecific antibodies capable of binding CD3 and a target antigen have also been proposed for therapeutic uses, including targeting the T cell immune response to tissues and cells expressing the target antigen.

CD20 is a non-glycosylated phosphoprotein expressed on the cell membrane of mature B cells. CD20 is considered a B-cell tumor-associated antigen because it is expressed by more than 95% of B-cell non-Hodgkin's lymphoma (NHL) and other B-cell malignancies, but is absent on precursor B-cells, dendritic cells and plasma cells. is considered Methods of treating cancer by targeting CD20 are known in the art. For example, the chimeric anti-CD20 monoclonal antibody rituximab has been used or proposed for use in the treatment of cancers such as NHL, chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). . CD20 is thought to kill CD20-expressing tumor cells by induction of complement dependent cytotoxicity (CDC), antibody-dependent cell mediated cytotoxicity (ADCC) and/or apoptosis and sensitization to chemotherapy. Although anti-CD20 tumor targeting strategies have been shown to be very promising in the clinical setting, not all patients respond to anti-CD20 therapy, and some patients develop resistance to or incomplete response to anti-CD20 therapy ( e.g. For example , it was found to exhibit resistance to rituximab).

Bispecific antigen-binding molecules that bind both CD3 and a target antigen (eg, CD20) may be useful in therapeutic settings where specific targeting and T-cell mediated killing of cells expressing the target antigen is desired. have.

In a first aspect, the present invention provides antibodies and antigen-binding fragments thereof that bind human CD3. Antibodies according to this aspect of the invention are useful, inter alia , for targeting T cells that express CD3, and for stimulating T cell activation, for example under circumstances where T cell-mediated killing is beneficial or desirable. . The anti-CD3 antibody, or antigen-binding portion thereof, of the present invention, as part of a bispecific antibody that directs CD3-mediated T cell activation against a specific cell type, eg, a tumor cell or an infectious agent, can be included

Exemplary anti-CD3 antibodies of the invention are listed in Tables 1 and 2 herein. Table 1 shows the amino acids of the heavy chain variable regions (HCVR) and light chain variable regions (LCVR) and heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) of exemplary anti-CD3 antibodies. Provide sequence identifiers. Table 2 shows sequence identifiers of nucleic acid molecules encoding HCVR, LCVR, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of exemplary anti-CD3 antibodies.

The present invention relates to sequences selected from any of the HCVR amino acid sequences listed in Table 1, or substantially similar sequences thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity to these sequences. An antibody, or antigen-binding fragment thereof, comprising an HCVR comprising an amino acid sequence is provided.

In addition, the present invention provides any of the LCVR amino acid sequences listed in Table 1, or substantially similar sequences thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to these sequences. An antibody, or antigen-binding fragment thereof, comprising an LCVR comprising an amino acid sequence selected from

In addition, the present invention provides an HCVR and LCVR amino acid sequence pair (HCVR/LCVR) comprising any of the HCVR amino acid sequences listed in Table 1 paired with any of the LCVR amino acid sequences listed in Table 1. Antibodies, or antigen-binding fragments thereof, comprising According to certain embodiments, the present invention provides an antibody, or antigen-binding fragment thereof, comprising the HCVR/LCVR amino acid sequence pair contained in any of the exemplary anti-CD3 antibodies listed in Table 1 . In certain embodiments, the HCVR/LCVR amino acid sequence pair is SEQ ID NO: 2/10 ( eg , H1H2712N); 114/122 ( eg , H2M2609N); 514/522 ( eg , H2M3563N); 770/778 ( eg , H1H5778P); 1050/1234 ( eg H1H7195B); and 1090/1234 ( eg , H1H7208B).

In addition, the present invention provides an amino acid sequence selected from any of the HCDR1 amino acid sequences listed in Table 1, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. Provides an antibody, or antigen-binding fragment thereof, comprising a heavy chain CDR1 (HCDR1) comprising a.

In addition, the present invention provides an amino acid sequence selected from any of the HCDR2 amino acid sequences listed in Table 1, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. Provides an antibody, or antigen-binding fragment thereof, comprising a heavy chain CDR2 (HCDR2) comprising a.

In addition, the present invention provides an amino acid sequence selected from any of the HCDR3 amino acid sequences listed in Table 1, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. Provides an antibody, or antigen-binding fragment thereof, comprising a heavy chain CDR3 (HCDR3) comprising a.

In addition, the present invention provides an amino acid sequence selected from any of the LCDR1 amino acid sequences listed in Table 1, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. Provides an antibody, or antigen-binding fragment thereof, comprising a light chain CDR1 (LCDR1) comprising a.

In addition, the present invention provides an amino acid sequence selected from any of the LCDR2 amino acid sequences listed in Table 1, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. Provides an antibody, or antigen-binding fragment thereof, comprising a light chain CDR2 (LCDR2) comprising a.

In addition, the present invention provides an amino acid sequence selected from any of the LCDR3 amino acid sequences listed in Table 1, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. Provides an antibody, or antigen-binding fragment thereof, comprising a light chain CDR3 (LCDR3) comprising a.

In addition, the present invention provides a HCDR3 and LCDR3 amino acid sequence pair (HCDR3/LCDR3) comprising any of the HCDR3 amino acid sequences listed in Table 1 paired with any of the LCDR3 amino acid sequences listed in Table 1. It provides an antibody, or antigen-binding fragment thereof, comprising a. According to certain embodiments, the present invention provides an antibody, or antigen-binding fragment thereof, comprising the HCDR3/LCDR3 amino acid sequence pair contained in any of the exemplary anti-CD3 antibodies listed in Table 1 . In certain embodiments, the HCDR3/LCDR3 amino acid sequence pair is SEQ ID NO: 8/16 ( eg , H1H2712N); 120/128 ( eg H2M2609N); 520/528 ( eg , H2M3563N); 776/784 ( eg , H1H5778P); 1056/1240 ( eg , H1H7195B); and 1096/1240 ( eg , H1H7208B).

The invention also provides an antibody comprising a set of six CDRs ( i.e. , HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within any of the exemplary anti-CD3 antibodies listed in Table 1. , or an antigen-binding fragment thereof. In certain embodiments, the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 set of amino acid sequences comprises SEQ ID NO: 4-6-8-12-14-16 ( eg , H1H2712N); 116-118-120-124-126-128 ( eg , H2M2609N); 516-518-520-524-526-528 ( eg , H2M3563N); 772-774-776-780-782-784 ( eg , H1H5778P); 1052-1054-1056-1236-1238-1240 ( eg , H1H7195B); and 1092-1094-1096-1236-1238-1240 ( eg , H1H7208B).

In a related embodiment, the invention provides a set of six CDRs contained within a HCVR/LCVR amino acid sequence pair as defined by any of the exemplary anti-CD3 antibodies listed in Table 1 ( i.e. , HCDR1- HCDR2-HCDR3-LCDR1-LCDR2-LCDR3), an antibody, or an antigen-binding fragment thereof. For example, the present invention relates to SEQ ID NO: 2/10 ( eg , H1H2712N); 114/122 ( eg , H2M2609N); 514/522 ( eg , H2M3563N); 770/778 ( eg , H1H5778P); 1050/1234 ( eg H1H7195B); and 1090/1234 ( e.g. , H1H7208B), wherein the antibody, or antigen thereof, comprises the set of HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequences contained within an HCVR/LCVR amino acid sequence pair selected from the group consisting of: Contains binding fragments. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within specified HCVR and/or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify the boundaries of CDRs include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general terms, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, eg , Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al. , J. Mol. Biol. 273 :927-948 (1997); and Martin et al. , Proc. Natl. Acad. Sci. USA 86 :9268-9272 (1989) ] . Public databases are also available for identifying CDR sequences within antibodies.

The present invention also provides nucleic acid molecules encoding anti-CD3 antibodies or portions thereof. For example, the present invention provides nucleic acid molecules encoding any of the HCVR amino acid sequences listed in Table 1; In certain embodiments the nucleic acid molecule is any of the HCVR nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity to them. It includes a polynucleotide sequence selected from.

The present invention also provides nucleic acid molecules encoding any of the LCVR amino acid sequences listed in Table 1; In certain embodiments the nucleic acid molecule is any of the LCVR nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity to them. It includes a polynucleotide sequence selected from.

The present invention also provides nucleic acid molecules encoding any of the HCDR1 amino acid sequences listed in Table 1; In certain embodiments, the nucleic acid molecule is any of the HCDR1 nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to them. It includes a polynucleotide sequence selected from.

The present invention also provides nucleic acid molecules encoding any of the HCDR2 amino acid sequences listed in Table 1; In certain embodiments, the nucleic acid molecule is any of the HCDR2 nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to them. It includes a polynucleotide sequence selected from.

The present invention also provides nucleic acid molecules encoding any of the HCDR3 amino acid sequences listed in Table 1; In certain embodiments, the nucleic acid molecule is any of the HCDR3 nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to them. It includes a polynucleotide sequence selected from.

The present invention also provides nucleic acid molecules encoding any of the LCDR1 amino acid sequences listed in Table 1; In certain embodiments the nucleic acid molecule is any of the LCDR1 nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity to them. It includes a polynucleotide sequence selected from.

The present invention also provides nucleic acid molecules encoding any of the LCDR1 amino acid sequences listed in Table 1; In certain embodiments the nucleic acid molecule is any of the LCDR1 nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity to them. It includes a polynucleotide sequence selected from.

The present invention also provides nucleic acid molecules encoding any of the LCDR2 amino acid sequences listed in Table 1; In certain embodiments the nucleic acid molecule is any of the LCDR2 nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity to them. It includes a polynucleotide sequence selected from.

The present invention also provides nucleic acid molecules encoding any of the LCDR3 amino acid sequences listed in Table 1; In certain embodiments the nucleic acid molecule is any of the LCDR3 nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity to them. It includes a polynucleotide sequence selected from.

The present invention also provides a nucleic acid molecule encoding an HCVR, wherein the HCVR comprises a set of three CDRs ( i.e. , HCDR1-HCDR2-HCDR3), wherein the HCDR1-HCDR2-HCDR3 amino acid sequence set is , as defined by any of the exemplary anti-CD3 antibodies listed in Table 1.

The present invention also provides a nucleic acid molecule encoding an LCVR, wherein the LCVR comprises a set of three CDRs ( i.e. , LCDR1-LCDR2-LCDR3), wherein the LCDR1-LCDR2-LCDR3 set of amino acid sequences is , as defined by any of the exemplary anti-CD3 antibodies listed in Table 1.

The present invention also provides a nucleic acid molecule encoding both HCVR and LCVR, wherein the HCVR comprises an amino acid sequence of any of the HCVR amino acid sequences listed in Table 1, wherein the LCVR is , the amino acid sequence of any of the LCVR amino acid sequences listed in Table 1. In certain embodiments, the nucleic acid molecule is substantially identical to any of the HCVR nucleic acid sequences listed in Table 2, or those having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to them. polynucleotide sequences selected from similar sequences, and any of the LCVR nucleic acid sequences listed in Table 2, or substantially those having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to them polynucleotide sequences selected from similar sequences. In certain embodiments according to this aspect of the invention, said nucleic acid molecules encode HCVRs and LCVRs, wherein said HCVRs and LCVRs are both derived from the same anti-CD3 antibody listed in Table 1.

In addition, the present invention provides a recombinant expression vector capable of expressing a polypeptide comprising a heavy or light chain variable region of an anti-CD3 antibody. For example, the present invention provides recombinant nucleic acid molecules comprising any of the aforementioned nucleic acid molecules, i.e. , a nucleic acid molecule encoding any of the HCVR, LCVR, and/or CDR sequences set forth in Table 1. Contains expression vectors. Host cells into which these vectors have been introduced, and methods for producing antibodies or parts thereof by culturing the host cells under conditions allowing production of antibodies or antibody fragments and recovering the antibodies and antibody fragments thus produced are also described in the present invention. included within the scope.

The present invention includes anti-CD3 antibodies with altered glycosylation patterns. In some embodiments, modifications to remove undesirable glycosylation sites or fucose moieties present on the oligosaccharide chains, e.g., to increase antibody-dependent cellular cytotoxicity (ADCC) function, are Antibodies lacking may be useful (see Shield et al. (2002) JBC 277:26733). In other applications, modification of galactosylation can be made to modify complement dependent cytotoxicity (CDC).

In another aspect, the invention provides a pharmaceutical composition comprising a recombinant human antibody or fragment thereof that specifically binds CD3 and a pharmaceutically acceptable carrier. In a related aspect, the invention features a composition that is a combination of an anti-CD3 antibody and a second therapeutic agent. In one embodiment, the second therapeutic agent is any agent that is advantageously combined with an anti-CD3 antibody. Exemplary agents that may be advantageously combined with an anti-CD3 antibody include other agents that bind to and/or activate CD3 signaling (including other antibodies or antigen-binding fragments thereof, etc.) and/or that directly target CD3. Agents that do not bind but nonetheless activate or stimulate immune cell activation are included, but are not limited to these. Additional combination therapies and co-formulations comprising the anti-CD3 antibodies of the invention are disclosed elsewhere herein.

In another aspect, the invention provides a therapeutic method for stimulating T cell activation using an anti-CD3 antibody or antigen-binding portion of an antibody of the invention, wherein the therapeutic method is in need of treatment. and administering a therapeutically effective amount of a pharmaceutical composition comprising an antibody or antigen-binding fragment of an antibody of the invention to a subject. The disorder being treated is any disease or condition that is enhanced, ameliorated, inhibited, or prevented by stimulation of CD3 activity or signaling.

According to another aspect, the present invention provides a bispecific antigen-binding molecule that binds CD3 and a target antigen. According to certain exemplary embodiments, the bispecific antigen-binding molecule binds CD3 and CD20; Such bispecific antigen-binding molecules are also referred to herein as “anti-CD3/anti-CD20 bispecific molecules”. The anti-CD3/anti-CD20 anti-CD20 portion of the bispecific molecule is useful for targeting tumor cells that express CD20 ( eg , B-cell tumors), and the anti-CD3 of the bispecific molecule is useful for targeting T-cells. useful for activating The simultaneous binding of CD20 on tumor cells and CD3 on T-cells enables directed killing (cell lysis) of targeted tumor cells by activated T-cells. Thus, among others , the anti-CD3/anti-CD20 bispecific molecules of the present invention are useful for treating diseases and disorders associated with or caused by CD20-expressing tumors ( eg , lymphomas).

A bispecific antigen-binding molecule according to this aspect of the invention comprises a first antigen-binding domain that specifically binds human CD3, and a second antigen-binding domain that specifically binds CD20. The present invention includes anti-CD3/anti-CD20 bispecific molecules ( eg, bispecific antibodies), wherein each antigen-binding domain is a heavy chain variable region paired with a light chain variable region (LCVR). (HCVR). In certain exemplary embodiments of the invention, the anti-CD3 antigen-binding domain and the anti-CD20 antigen binding domain each comprise different and distinct HCVRs paired with a common LCVR. For example, as demonstrated in Example 7 herein, a first antigen-binding domain that specifically binds to CD3, wherein the first antigen-binding domain is a HCVR/LCVR derived from an anti-CD3 antibody includes pairs); and a second antigen-binding domain that specifically binds to CD20, wherein the second antigen-binding domain is an LCVR derived from an anti-CD3 antibody ( e.g., the same antibody included in the anti-CD3 antigen-binding domain). A bispecific antibody was constructed, comprising a HCVR derived from an anti-CD20 antibody paired with a LCVR). That is, in an exemplary molecule disclosed herein, pairing of an LCVR from an anti-CD3 antibody with an HCVR from an anti-CD20 antibody binds specifically to CD20 (but not to CD3). not) to create an antigen-binding domain. In this embodiment, the first and second antigen-binding domains include separate anti-CD3 and anti-CD20 HCVRs, but share a common anti-CD3 LCVR.

The present invention provides an anti-CD3/anti-CD20 bispecific molecule, wherein a first antigen-binding domain that specifically binds to CD3 is any of the HCVR amino acid sequences set forth in Table 1 or Table 18. contains sequence. In addition, the first antigen-binding domain that specifically binds to CD3 may include any of the LCVR amino acid sequences shown in Table 1 or Table 19. According to certain embodiments, the first antigen-binding domain that specifically binds CD3 comprises any of the HCVR/LCVR amino acid sequence pairs set forth in Table 1 or Table 17. The present invention also provides an anti-CD3/anti-CD20 bispecific molecule, wherein a first antigen-binding domain that specifically binds to CD3 comprises a heavy chain CDR1-CDR2- as shown in Table 1 or Table 18. any of the CDR3 amino acid sequences, and/or any of the light chain CDR1-CDR2-CDR3 amino acid sequences set forth in Table 1 or Table 19.

According to certain embodiments, the present invention provides an anti-CD3/anti-CD20 bispecific molecule, wherein a first antigen-binding domain that specifically binds to CD3 is SEQ ID NO: 1250, 1266, 1282, 1298; a heavy chain variable region (HCVR) having an amino acid sequence selected from an amino acid sequence selected from the group consisting of 1314 and 1329, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity; includes

The present invention also provides an anti-CD3/anti-CD20 bispecific molecule, wherein the first antigen-binding domain that specifically binds to CD3 has SEQ ID NOs: 1258, 1274, 1290, 1306, 1322 and 1333 a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of:

The present invention also provides an anti-CD3/anti-CD20 bispecific molecule, wherein the first antigen-binding domain that specifically binds to CD3 has SEQ ID NOs: 1250/1258, 1266/1274, 1282/1290; HCVR and LCVR (HCVR/LCVR) amino acid sequence pairs selected from the group consisting of 1298/1306, 1314/1322, and 1329/1333.

The present invention also provides an anti-CD3/anti-CD20 bispecific molecule, wherein the first antigen-binding domain that specifically binds to CD3 has SEQ ID NOs: 1256, 1272, 1288, 1304, 1320 and 1332 a heavy chain CDR3 (HCDR3) having an amino acid sequence selected from the group consisting of, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; and an amino acid sequence selected from the group consisting of SEQ ID NOs: 1264, 1280, 1296, 1312, 1328 and 1336, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. light chain CDR3 (LCDR3).

In certain embodiments, the first antigen-binding domain that specifically binds CD3 is selected from the group consisting of SEQ ID NOs: 1256/1264, 1272/1280, 1288/1296, 1304/1312, 1320/1328 and 1332/1336 HCDR3/LCDR3 amino acid sequence pair.

The present invention also provides an anti-CD3/anti-CD20 bispecific antigen-binding molecule, wherein the first antigen-binding domain that specifically binds to CD3 is SEQ ID NO: 1252, 1268, 1284, 1300, 1316 and 1330, or a heavy chain CDR1 (HCDR1) domain having an amino acid sequence selected from the group consisting of, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity; a heavy chain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1254, 1270, 1286, 1302, 1318 and 1331, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; CDR2 (HCDR2) domain; A light chain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1260, 1276, 1292, 1308, 1324 and 1334, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. CDR1 (LCDR1) domain; and an amino acid sequence selected from the group consisting of SEQ ID NOs: 1262, 1278, 1294, 1310, 1326 and 1335, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. light chain CDR2 (LCDR2) domain.

Certain non-limiting examples of anti-CD3/anti-CD20 bispecific antigen-binding molecules of the present invention include SEQ ID NOs: 1252-1254-1256-1260-1262-1264 ( eg , BS3/20-001); 1268-1270-1272-1276-1278-1280 ( eg , BS3/20-002); 1284-1286-1288-1292-1294-1296 ( eg , BS3/20-003); 1300-1302-1304-1308-1310-1312 ( eg , BS3/20-004); 1316-1318-1320-1324-1326-1328 ( eg , BS3-20-005); and 1330-1331-1332-1334-1335-1336 ( eg , BS3/20-007) HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains each having an amino acid sequence selected from the group consisting of: and a first antigen-binding domain that specifically binds to.

The present invention also provides an anti-CD3/anti-CD20 bispecific molecule, wherein the second antigen-binding domain that specifically binds to CD20 comprises the amino acid sequence of SEQ ID NO: 1242, or at least 90%, 95% a heavy chain variable region (HCVR) having a substantially similar sequence thereof having at least 98% or at least 99% sequence identity.

The present invention also provides an anti-CD3/anti-CD20 bispecific molecule, wherein the second antigen-binding domain that specifically binds to CD20 has SEQ ID NOs: 1258, 1274, 1290, 1306, 1322 and 1333 a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of:

The present invention also provides an anti-CD3/anti-CD20 bispecific molecule, wherein the second antigen-binding domain that specifically binds to CD20 comprises SEQ ID NOs: 1242/1258, 1242/1274, 1242/1290; HCVR and LCVR (HCVR/LCVR) amino acid sequence pairs selected from the group consisting of 1242/1306, 1242/1322 and 1242/1333.

The present invention also provides an anti-CD3/anti-CD20 bispecific molecule, wherein the second antigen-binding domain that specifically binds to CD20 comprises the amino acid sequence of SEQ ID NO: 1248, or at least 90%, 95% a heavy chain CDR3 (HCDR3) domain having a substantially similar sequence thereof having at least 98% or at least 99% sequence identity; and an amino acid sequence selected from the group consisting of SEQ ID NOs: 1264, 1280, 1296, 1312, 1328 and 1336, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. and a light chain CDR3 (LCDR3) domain.

In certain embodiments, the second antigen-binding domain that specifically binds CD20 is selected from the group consisting of SEQ ID NOs: 1248/1264, 1248/1280, 1248/1296, 1248/1312, 1248/1328 and 1248/1336 HCDR3/LCDR3 amino acid sequence pair.

The present invention also provides an anti-CD3/anti-CD20 bispecific antigen-binding molecule, wherein the second antigen-binding domain that specifically binds to CD20 comprises the amino acid sequence of SEQ ID NO: 1244, or 90% or more , a heavy chain CDR1 (HCDR1) domain having a substantially similar sequence thereof having at least 95%, at least 98%, or at least 99% sequence identity; a heavy chain CDR2 (HCDR2) domain having the amino acid sequence of SEQ ID NO: 1246, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity; A light chain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1260, 1276, 1292, 1308, 1324 and 1334, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. CDR1 (LCDR1); and an amino acid sequence selected from the group consisting of SEQ ID NOs: 1262, 1278, 1294, 1310, 1326 and 1335, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. light chain CDR2 (LCDR2).

Certain non-limiting examples of anti-CD3/anti-CD20 bispecific antigen-binding molecules of the present invention include SEQ ID NOs: 1244-1246-1248-1260-1262-1264 ( eg , BS3/20-001); 1244-1246-1248-1276-1278-1280 ( eg , BS3/20-002); 1244-1246-1248-1292-1294-1296 ( eg , BS3/20-003); 1244-1246-1248-1308-1310-1312 ( eg , BS3/20-004); 1244-1246-1248-1324-1326-1328 ( eg , BS3-20-005); and 1244-1246-1248-1334-1335-1336 ( e.g. , BS3/20-007) HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains each having an amino acid sequence selected from the group consisting of: and a second antigen-binding domain that specifically binds to.

In a related embodiment, the present invention includes an anti-CD3/anti-CD20 bispecific antigen-binding molecule, wherein the second antigen-binding domain that specifically binds CD20 is SEQ ID NO: 1242/1258, 1242/ 1274, 1242/1290, 1242/1306, 1242/1322 and 1242/1333, heavy and light chain CDR domains contained within heavy and light chain variable regions (HCVR/LCVR).

In another aspect, the present invention provides HCVRs of anti-CD3/anti-CD20 bispecific antigen-binding molecules disclosed herein, comprising nucleic acid molecules comprising the polynucleotide sequences set forth in Tables 20 and 21 herein; Nucleic acid molecules encoding any of the LCVR or CDR sequences, and nucleic acid molecules comprising two or more of the polynucleotide sequences set forth in Tables 20 and 21 in any functional combination or arrangement thereof are provided. Recombinant expression vectors carrying the nucleic acids of the present invention, and host cells into which such vectors have been introduced are also included in the present invention, and are capable of producing antibodies by culturing the host cells under conditions allowing production of antibodies and recovering the produced antibodies. Methods are also included in the present invention.

The present invention includes anti-CD3/anti-CD20 bispecific antigen-binding molecules, wherein any of the aforementioned antigen-binding domains that specifically bind to CD3 bind specifically to CD20. Combined, linked, or otherwise associated with any of the aforementioned antigen-binding domains to form a bispecific antigen-binding molecule that binds CD3 and CD20.

The present invention includes anti-CD3/anti-CD20 bispecific antigen-binding molecules with altered glycosylation patterns. For some applications, modifications to remove undesirable glycosylation sites may be useful, or, for example, fucose present on oligosaccharide chains to increase antibody-dependent cellular cytotoxicity (ADCC) function. Antibodies lacking the moiety may be useful (see Shield et al. (2002) JBC 277:26733). In other applications, modification of galactosylation can be made to modify complement dependent cytotoxicity (CDC).

In another aspect, the invention provides a pharmaceutical composition comprising an anti-CD3/anti-CD20 bispecific antigen-binding molecule disclosed herein and a pharmaceutically acceptable carrier. In a related aspect, the invention features a composition that is a combination of an anti-CD3/anti-CD20 bispecific antigen-binding molecule and a second therapeutic agent. In one embodiment, the second therapeutic agent is any agent that is advantageously combined with an anti-CD3/anti-CD20 bispecific antigen-binding molecule. Exemplary agents that can be advantageously combined with anti-CD3/anti-CD20 bispecific antigen-binding molecules are discussed in detail elsewhere herein.

In another aspect, the invention provides a therapeutic method for targeting/killing tumor cells expressing CD20 using an anti-CD3/anti-CD20 bispecific antigen-binding molecule of the invention, wherein the treatment The therapeutic method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an anti-CD3/anti-CD20 bispecific antigen-binding molecule of the present invention.

The present invention also includes the use of an anti-CD3/anti-CD20 bispecific antigen-binding molecule of the present invention in the manufacture of a medicament for the treatment of a disease or disorder associated with or caused by CD20 expression.

Other embodiments will become apparent from a review of the specific details for carrying out the invention.

1 : NOD implanted subcutaneously with a mixture of Raji tumor cells and PBMC following tumor implantation and treatment with human Fc (hFc, solid line) or CD3xCD20 bispecific antibody (BS3/20-007, dotted line) starting on the day of tumor implantation. / Represents tumor volume (mm 3 ) over time in SCID mice.
Figure 2 shows subcutaneous implantation of a mixture of Raji tumor cells and PBMCs following tumor implantation and treatment with human Fc (hFc, solid line) or CD3xCD20 bispecific antibody (BS3/20-007, dotted line) starting 7 days after tumor implantation. Tumor volume (mm 3 ) over time in NOD/SCID mice is shown.
Figure 3 : Bispecific antibody BS3/20-001 (0.01, 0.1 or 1.0 mg/kg); low dose anti-CD20 control antibody (Control V, 0.01 mg/kg); or B-cell counts (x1000 μL) over time in blood samples from cynomolgus monkeys treated with three different doses of high-dose anti-CD20 control antibody (Control III, 1.0 mg/kg).
Figure 4 : Bispecific antibody BS3/20-001 (0.01, 0.1 or 1.0 mg/kg); low dose anti-CD20 control antibody (Control V, 0.01 mg/kg); or T-cell counts (x1000 μL) over time in blood samples from cynomolgus monkeys treated with three different doses of high-dose anti-CD20 control antibody (Control III, 1.0 mg/kg).
5A , 5B , 5C and 5D show BS3/20-001 (0.01, 0.1 or 1.0 mg/kg), low dose anti-CD20 control antibody (0.01 mg/kg control V), or high dose anti-CD20 control Pre-dose and post-dose levels of IFN-gamma, IL-2, IL-6, and TNF-alpha (pg/mL) for cynomolgus monkeys treated with a single dose of antibody (1.0 mg/kg control III) ), respectively.
Figure 6 : Control V (anti-CD20 antibody) at 0.01 mg/kg; Control III (anti-CD20 antibody) at 1.0 mg/kg; and 0.01 mg/kg, 0.1 mg/kg, and 1.0 mg/kg of BS3/20-001 (anti-CD3xCD20 bispecific antibody). CD20 expression profile measured from blood samples drawn at various time points from cynomolgus monkeys treated (expressed in terms of log 2 fold change in expression).
Figure 7 : Time-lapse in blood samples from cynomolgus monkeys treated with 1.0 mg/kg (open triangles), 0.1 mg/kg (open squares) or 0.01 mg/kg (open diamonds) of the CD3xCD20 bispecific antibody. Total serum concentrations (μg/mL) of CD3xCD20 bispecific antibody (BS3/20-001) are shown.

Before describing the present invention, it should be understood that the present invention is not limited to the specific methods and experimental conditions described, as these may vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term "about" when used in reference to a particular recited numerical value means that the value may differ from the recited value by no more than 1%. For example, the expression "about 100" as used herein includes 99 and 101 and all values in between (eg, 99.1, 99.2, 99.3, 99.4, etc.).

Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described below.

Justice

As used herein, the expression "CD3" is expressed on T cells as part of the multimolecular T cell receptor (TCR) and is expressed on four receptor chains: CD3-epsilon, CD3-delta, CD3-zeta, and CD3-gamma. It refers to antigens composed of homodimers or heterodimers formed from two associations. Human CD3-epsilon comprises the amino acid sequence set forth in SEQ ID NO: 1370; Human CD3-delta comprises the amino acid sequence set forth in SEQ ID NO: 1371. All references herein to proteins, polypeptides and protein fragments are intended to refer to the human version of the respective protein, polypeptide or protein fragment, unless expressly specified as being from a non-human species. Thus, the expression "CD3" refers to human CD3 unless otherwise specified as being from a non-human species, eg , "mouse CD3", "monkey CD3", etc.

An “antibody that binds CD3” or “anti-CD3 antibody” as used herein refers to antibodies and antigens thereof that specifically recognize a single CD3 subunit ( eg , epsilon, delta, gamma or zeta). Antibodies and antigen-binding fragments thereof that specifically recognize binding fragments and dimeric complexes of two CD3 subunits ( eg , gamma/epsilon, delta/epsilon, and zeta/zeta CD3 dimers) include Antibodies and antigen-binding fragments of the invention are capable of binding soluble CD3 and/or cell surface expressed CD3. Soluble CD3 includes native CD3 protein and recombinant CD3 protein variants, such as monomeric and dimeric CD3 constructs, which lack the transmembrane domain or are otherwise not associated with the cell membrane.

As used herein, the expression “cell surface-expressed CD3” refers to an expression on the surface of a cell, either in vitro or in vivo, such that at least a portion of the CD3 protein is exposed to the extracellular side of the cell membrane and is accessible to the antigen-binding portion of the antibody. One or more CD3 protein(s) that are expressed. "Cell surface-expressed CD3" includes the CD3 protein contained within the context of a functional T cell receptor in the membrane of a cell. The expression “cell surface-expressed CD3” refers to a CD3 protein expressed as a homodimer or part of a heterodimer ( eg , gamma/epsilon, delta/epsilon, and zeta/zeta CD3 dimers) on the surface of a cell. includes The expression “cell surface-expressed CD3” also includes a CD3 chain that is expressed by itself in the absence of other CD3 chain types on the surface of a cell ( eg , CD3-epsilon, CD3-delta or CD3-gamma). . The expression “cell surface-expressed CD3” also includes a CD3 chain that is expressed by itself in the absence of other CD3 chain types on the surface of a cell ( eg , CD3-epsilon, CD3-delta or CD3-gamma). . “Cell surface-expressed CD3” may comprise or consist of a CD3 protein expressed on the surface of cells that normally express CD3 protein. Alternatively, “cell surface-expressed CD3” includes or includes CD3 protein expressed on the surface of a cell that does not normally express human CD3 on its surface but has been artificially engineered to express CD3 on its surface. May be composed of proteins.

As used herein, the expression "anti-CD3 antibody" refers to a monovalent antibody having a single specificity and a bispecific comprising a first arm that binds CD3 and a second arm that binds a second (target) antigen. both antibodies, wherein the anti-CD3 arm comprises any of the HCVR/LCVR or CDR sequences set forth in Table 1 or Tables 18/19 herein. Examples of anti-CD3 bispecific antibodies are described elsewhere herein. The term "antigen-binding molecule" includes antibodies and antigen-binding fragments of antibodies, including, for example , bispecific antibodies.

As used herein, the term "antibody" refers to any antigen-binding molecule or molecule comprising one or more complementarity determining regions (CDRs) that specifically binds or interacts with a particular antigen ( eg , CD3). means complex. The term "antibody" refers to an immunoglobulin molecule comprising four polypeptide chains, two heavy (H) chains and two light (L) chains, interconnected by disulfide bonds, and multimers thereof ( e.g. , IgM ). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V _H ) and a heavy chain constant region. The heavy chain constant region contains three domains, C _H 1 , C _H 2 and C _H 3 . Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V _L ) and a light chain constant region. The light chain constant region comprises one domain (C _L 1 ). The V _H and V _L regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each V _H and V _L is composed of three CDRs and four FRs arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the invention, the FRs of the antibodies (or antigen-binding portions thereof) may be identical to human germline sequences or may be naturally or artificially modified. An amino acid consensus sequence can be defined based on a side-by-side analysis of two or more CDRs.

Also, as used herein, the term “antibody” includes antigen-binding fragments of complete antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like refer to any naturally occurring polypeptide or glycoprotein, enzymatically Polypeptides or glycoproteins obtainable as, synthetic polypeptides or glycoproteins, or genetically engineered polypeptides or glycoproteins. Antigen-binding fragments of antibodies may be prepared by any suitable standard technique, eg, proteolytic digestion or recombinant genetic manipulation involving manipulation and expression of DNA encoding the antibody variable and optionally constant domains, for example , from the complete antibody molecule. can be derived using technology. Such DNA is known and/or readily available, eg , from commercial sources, DNA libraries ( including eg phage-antibody libraries), or can be synthesized. DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, introduce codons, create cysteine residues, or , Amino acids, etc. may be modified, added, or deleted.

Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragment; (iv) Fv fragment; (v) single-chain Fv (svFv) molecules; (vi) dAb fragments; and (vii) amino acid residues that mimic the hypervariable regions of antibodies ( eg, isolated complementarity determining regions (CDRs), such as CDR3 peptides), or minimal recognition units consisting of restricted FR3-CDR3-FR4 peptides. In addition, other engineered molecules such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies Bodies ( eg, monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains are also included within the expression "antigen-binding fragment" as used herein. .

An antigen-binding fragment of an antibody will typically include one or more variable domains. A variable domain can be of any size or composition of amino acids, and will generally comprise one or more CDRs, contiguous with or in frame with one or more framework sequences. In an antigen-binding fragment having a V _H domain associated with a V _L domain, the V _H and V _L domains may be positioned relative to each other in any suitable arrangement. For example, the variable region can be dimeric and contain V _H -V _H , V _H -V _L or V _L -V _L dimers. Alternatively, an antigen-binding fragment of an antibody may contain a monomeric V _H or V _L domain.

In certain embodiments, an antigen-binding fragment of an antibody may contain one or more variable domains covalently linked to one or more constant domains. Non-limiting exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present invention include: (i) V _H -C _H 1; (ii) V _{H -CH} 2; (iii) V _{H -CH} 3; (iv) V _H -C _H 1 -C _H 2; (v) V _H -C _H 1 -C _H 2 -C _H 3; (vi) V _H -C _H 2 -C _H 3; (vii) V _H -C _L ; (viii) V _L -C _H 1; (ix) V _{L -CH} 2; (x) V _{L -CH} 3; (xi) V _L -C _H 1 -C _H 2; (xii) V _L -C _H 1 -C _H 2 -C _H 3; (xiii) V _L -C _H 2 -C _H 3; and (xiv) V _L -C _L . In any configuration of the variable and constant domains, including any of the configurations of the examples enumerated above, the variable and constant domains may be directly linked to each other, or a complete or partial hinge or linker region can be linked by A hinge region can be two or more (e.g., 5, 10, 10, 10, 10, 12, 12, 12, 12, 12, 12, 12, 25, 25, 25, 20, 20, 20, 20, 23, or 20 or 25, 10, 20, 20, 23, 23, 28, 20, 10, 10, 10, 10, 10, 10 or 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10, 10 or more 15, 20, 40, 60 or more) amino acids. In addition, antigen-binding fragments of the antibodies of the present invention may be homo-dimers or hetero-dimers (or other multimers) of any of the variable and constant domain configurations listed above, with each other and/or one may include in non-covalent association ( eg , by disulfide bond(s)) with one or more monomeric V _H or V _L domains.

With respect to full antibody molecules, antigen-binding fragments may be monospecific or multispecific ( eg bispecific). A multispecific antigen-binding fragment of an antibody will typically comprise two or more different variable domains, wherein each variable domain can specifically bind to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, can be adapted for use in the context of an antigen-binding fragment of an antibody of the invention using routine techniques available in the art. have.

Antibodies of the invention may function through complement-dependent cytotoxicity (CDC) or antibody-dependent cell-mediated cytotoxicity (ADCC). "Complement-dependent cytotoxicity" (CDC) refers to the lysis of antigen-expressing cells by an antibody of the invention in the presence of complement. "Antibody-dependent cell-mediated cytotoxicity" (ADCC) is a term in which non-specific cytotoxic cells expressing Fc receptors (FcRs) ( eg , natural killer (NK) cells, neutrophils, and macrophages) refers to a cell-mediated reaction that results in lysis of target cells by recognizing antibodies bound to the phase. CDC and ADCC can be measured using assays that are well known and available in the art. (See, eg, US Pat. Nos. 5,500,362 and 5,821,337, and Clynes et al. (1998) Proc. Natl. Acad. Sci. (USA) 95 :652-656). The constant region of an antibody is important to the antibody's ability to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of an antibody may be selected based on whether mediating cytotoxicity is desired for the antibody.

In certain embodiments of the invention, the anti-CD3 antibodies (monospecific or bispecific) of the invention are human antibodies. As used herein, the term “human antibody” is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies of the present invention may be prepared by, for example, in the CDRs and in particular CDR3 amino acid residues not encoded by human germline immunoglobulin sequences (eg, by random or site-specific mutagenesis in vitro or in vivo somatic cell mutations introduced by mutation). However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

In some embodiments, an antibody of the invention may be a recombinant human antibody. As used herein, the term "recombinant human antibody" refers to any human antibody produced, expressed, generated or isolated by recombinant means, e.g., an antibody expressed using a recombinant expression vector transfected into a host cell (see below). described further), antibodies isolated from recombinant combinatorial human antibody libraries (described further below), antibodies isolated from animals (eg, mice) transgenic for human immunoglobulin genes (eg, mice). , Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or any other means involving splicing of human immunoglobulin gene sequences to other DNA sequences. It is intended to include antibodies produced, expressed, produced or isolated by. These recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are mutagenized in vitro (or, if animals transgenic for human Ig sequences are used, somatically mutated in vivo ), and thus the recombinant antibody's V _H and The amino acid sequence of the V _L region is a sequence that, although derived from and related to human germline V _H and V _L sequences, cannot naturally exist within the human antibody germline repertoire in vivo .

Human antibodies can exist in two forms related to hinge heterogeneity. In one form, an immunoglobulin molecule comprises a stable four-chain construct of approximately 150-160 kDa in which dimers are anchored by interchain heavy-chain disulfide bonds. In the second form, the dimers are not linked via interchain disulfide bonds, and the molecule of about 75 to 80 kDa consists of covalently coupled light and heavy chains (half-antibodies). These forms were very difficult to isolate even after affinity purification.

The frequency of occurrence of the second form in various intact IgG isotypes is due to, but not limited to, structural differences related to the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form to levels typically observed using the human IgG1 hinge (Angal et al. (1993) Molecular Immunology 30:105 ). The invention includes antibodies having one or more mutations in the hinge, C _H 2 or C _H 3 region, which may be desirable, for example, to improve yield of the desired antibody form upon production.

The antibody of the present invention may be an isolated antibody. “Isolated antibody,” as used herein, refers to an antibody that has been identified, separated, and/or recovered from one or more components of the antibody's natural environment. For example, an antibody that has been separated or removed from one or more components of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced, is an "isolated antibody" for purposes of the present invention. Also, isolated antibodies include in situ antibodies in recombinant cells. An isolated antibody is an antibody that has been subjected to one or more purification or isolation steps. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and/or chemicals.

In addition, the present invention includes a one-armed antibody that binds to CD3. As used herein, “one-arm antibody” refers to an antigen-binding molecule comprising a single antibody heavy chain and a single antibody light chain. A one-armed antibody of the present invention may comprise any of the HCVR/LCVR or CDR amino acid sequences set forth in Table 1 or Tables 18/19 herein.

The anti-CD3 antibodies disclosed herein have one or more amino acid substitutions, insertions, and/or deletions in the framework and/or CDR regions of the heavy and light chain variable domains, compared to the corresponding germline sequence from which these antibodies were derived. can include Such mutations can be readily identified, for example, by comparing the amino acid sequences disclosed herein to germline sequences available from public antibody sequence databases. The present invention includes antibodies, and antigen-binding fragments thereof, derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are The antibodies are mutated to the corresponding residue(s) of the derived germline sequence, or to the corresponding residue(s) of another human germline sequence, or to conservative amino acid substitutions of the corresponding germline residue(s) (such Sequence changes are collectively referred to herein as “germline mutations”). Starting with the heavy and light chain variable region sequences disclosed herein, one of ordinary skill in the art can readily generate a large number of antibodies and antigen-binding fragments comprising one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and/or CDR residues within the V _H and/or V _L domains are back mutated to residues found in the original germline sequence from which the antibody was derived. In another embodiment, only certain residues are mutated residues found, for example , within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or within CDR1, CDR2, or CDR3. Only the mutated residues are mutated back to the original germline sequence. In another embodiment, one or more of the framework and/or CDR residue(s) is mutated to the corresponding residue(s) in a different germline sequence ( ie , a germline sequence different from the germline sequence from which the antibody was originally derived). In addition, an antibody of the invention may contain any combination of two or more germline mutations within the framework and/or CDR regions, e.g., wherein certain individual residues are relative to corresponding residues in a particular germline sequence. While mutated, certain other residues that differ from the original germline sequence are either retained or mutated to corresponding residues in the different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations may exhibit one or more desirable properties, e.g., improved binding specificity, increased binding affinity, improved or enhanced antagonist or agonist biological properties (if any). ), can be easily tested for reduced immunogenicity and the like. Antibodies and antigen-binding fragments obtained in this general manner are included within the present invention.

The present invention also includes anti-CD3 antibodies comprising variants of any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein that have one or more conservative substitutions. For example, the present invention relates to any of the HCVR, LCVR, and/or CDR amino acid sequences set forth in Table 1 herein, for example, 10 or less, 8 or less, 6 or less, 4 or less Includes anti-CD3 antibodies having HCVR, LCVR, and/or CDR amino acid sequences with conservative amino acid substitutions, such as below.

The term "epitope" refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule, known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different regions on an antigen and may have different biological effects. Epitopes can be conformational or linear. Conformational epitopes are produced by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. A linear epitope is an epitope made by contiguous amino acid residues within a polypeptide chain. In certain circumstances, an epitope may include moieties of saccharides, phosphoryl groups, or sulfonyl groups on an antigen.

The term "substantially identical" or "substantially identical" when referring to nucleic acids or fragments thereof, refers to any well-known sequence identity when optimally aligned with appropriate nucleotide insertions or deletions to other nucleic acids (or complementary strands thereof). At least about 95%, more preferably at least about 96%, 97%, 98%, or 99% of the nucleotide bases as measured by a known algorithm, such as FASTA, BLAST, or Gap, as discussed below. Indicates the presence of % nucleotide sequence identity. A nucleic acid molecule having substantial identity to a reference nucleic acid molecule may, in certain instances, encode a polypeptide having the same or substantially similar amino acid sequence as a polypeptide encoded by the reference nucleic acid molecule.

The term “substantial similarity” or “substantially similar” as applied to polypeptides is at least 95% if two peptide sequences are optimally aligned, for example by the programs GAP or BESTFIT using default gap weights. of sequence identity, even more preferably at least 98% or 99% sequence identity. Preferably, residue positions that are not identical differ by conservative amino acid substitutions. A "conservative amino acid substitution" is one that is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (eg, charge or hydrophobicity). In general, conservative amino acid substitutions will not substantially alter the functional properties of a protein. When two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity can be adjusted upward to correct for the conservative nature of the substitutions. Means for making this adjustment are well known to those skilled in the art. See, eg , Pearson (1994) Methods Mol Biol 24: 307-331, incorporated herein by reference. Examples of groups of amino acids having side chains with similar chemical properties include (1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; (2) aliphatic-hydroxyl side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartate and glutamate, and (7) sulfur-containing side chains: cysteine and methionine. Preferred conservative amino acid substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. Alternatively, conservative replacements are described in Gonnet et al. (1992) Science 256: 1443-1445] is any change with a positive value in the PAM250 log-likelihood matrix. A “moderately conservative” replacement is any change with a non-negative value in the PAM250 log-likelihood matrix.

Sequence similarity for polypeptides, also referred to as sequence identity, is typically determined using sequence analysis software. Protein analysis software uses measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions, to match similar sequences. For example, GCG software can detect sequence homology or sequence identity between closely related polypeptides, e.g., homologous polypeptides from different species of organisms, or between a wild-type protein and its muteins. It contains programs that can be used with default parameters to measure, eg Gap and Bestfit. See, eg, GCG version 6.1. Polypeptide sequences can also be compared using FASTA using default or recommended parameters, a program in GCG version 6.1. FASTA (eg, FASTA2 and FASTA3) provides alignment and percent sequence identity of the region of highest overlap between query and search sequences (Pearson (2000) supra). Another preferred algorithm for comparing sequences of the present invention to a database containing a large number of sequences from different organisms is the computer program BLAST, particularly BLASTP or TBLASTN, using default parameters. See, eg, Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul et al. (1997) Nucleic Acids Res 25:3389-402.

Bispecific antigen-binding molecule

Antibodies of the present invention may be monospecific, bispecific, or multispecific. Multispecific antibodies may be specific for different epitopes of one target polypeptide or may contain antigen-binding domains for more than one target polypeptide. See, eg, Tutt et al., 1991, J. Immunol. 147:60-69; Kufer et al ., 2004, Trends Biotechnol. 22:238-244]. Anti-CD3 antibodies of the present invention may be linked to or co-expressed with other functional molecules, such as other peptides or proteins. For example, an antibody or fragment thereof may be incorporated into one or more other molecular entities, such as other antibodies or antibody molecules (e.g., chemical coupling, genetic fusion, non-covalent association or otherwise). ) to produce bispecific or multispecific antibodies having a second binding specificity.

Use of the expression “anti-CD3 antibody” herein is intended to include both monospecific anti-CD3 antibodies and bispecific antibodies comprising a CD3-binding arm and a second arm that binds a target antigen. Accordingly, the present invention includes bispecific antibodies wherein one arm of an immunoglobulin binds human CD and the other arm of an immunoglobulin is specific for a target antigen. The target to which the other arm of the CD3 bispecific antibody binds can be any antigen expressed on or in the vicinity of a cell, tissue, organ, microorganism or virus for which a targeted immune response is desired. The CD3-binding arm may comprise any of the HCVR/LCVR or CDR amino acid sequences set forth in Table 1 or Tables 18/19 herein. In certain embodiments, the CD3-binding arm binds human CD3 and induces human T cell proliferation.

With respect to a bispecific antibody of the invention wherein one arm of the antibody binds CD3 and the other arm binds a target antigen, the target antigen may be a tumor-associated antigen. Non-limiting examples of specific tumor-associated antigens include, for example , AFP, ALK, BAGE protein, β-catenin, brc-abl, BRCA1, BORIS, CA9, carbonic anhydrase IX, caspase-8, CCR5 , CD19, CD20, CD30, CD40, CDK4, CEA, CTLA4, Cyclin-B1, CYP1B1, EGFR, EGFRvIII, ErbB2/Her2, ErbB3, ErbB4, ETV6-AML, EpCAM, EphA2, Fra-1, FOLR1, GAGE proteins ( For example , GAGE-1, -2), GD2, GD3, GloboH, Glypican-3, GM3, gp100, Her2, HLA/B-raf, HLA/k-ras, HLA/MAGE-A3, hTERT, LMP2 , MAGE proteins ( eg , MAGE-1, -2, -3, -4, -6, and -12), MART-1, mesothelin, ML-IAP, Muc1, Muc2, Muc3, Muc4, Muc5, Muc16 (CA-125), MUM1, NA17, NY-BR1, NY-BR62, NY-BR85, NY-ESO1, OX40, p15, p53, PAP, PAX3, PAX5, PCTA-1, PLAC1, PRLR, PRAME, PSMA (FOLH1), RAGE proteins, Ras, RGS5, Rho, SART-1, SART-3, Steap-1, Steap-2, Servivin, TAG-72, TGF-β, TMPRSS2, Tn, TRP-1, TRP- 2, tyrosinase, and uroplakin-3.

With regard to a bispecific antibody of the invention wherein one arm of the antibody binds CD3 and the other arm binds a target antigen, the target antigen may be an infectious disease-associated antigen. Non-limiting examples of infectious disease-associated antigens include, for example , antigens expressed on the surface of viral particles or preferentially expressed on cells infected with the virus, wherein the virus is HIV, hepatitis (A, B or C), herpes virus ( e.g. , HSV-1, HSV-2, CMV, HAV-6, VZV, Epstein Barr virus), adenovirus, influenza virus, flavivirus, echovirus, Rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV, dengue virus, papilloma virus, continuum virus, poliovirus, rabies virus, JC virus, and arboviral encephalitis virus. Alternatively, the target antigen may be an antigen expressed on the surface of a bacterium or preferentially expressed on a cell infected with a bacterium, wherein the bacterium is Chlamydia, Rickettsia, Mycobacteria, Staphylococcus, Streptococcus, Pneumococcus, Meningococcus, Gonococcus, Klebsiella, Proteus, Serratia, Pseudomonas, Legionella, Diphtheria, Salmonella, Bacillus, Cholera, Tetanus, Botulism, Anthrax, Plaque, Leptospira, and Lyme disease bacteria selected from the group. In certain embodiments, the target antigen is an antigen that is expressed on the surface of a fungus or preferentially expressed on cells infected with the fungus, wherein the fungus is Candida (Albicans, Krusei, Glabrata, Trophy) Callis, etc.), Cryptococcus neoformans, Aspergillus (Fumigatus, Niger, etc.), Mucorales (Mucor, Apsidia, Rhizopus, etc.), Sporotrix Schenckii, Blasto It is selected from the group consisting of Myces dermatitidis, Paracoccidioides brasiliensis, Coccidioides imitis, and Histoplasma capsulatum. In certain embodiments, the target antigen is an antigen expressed on the surface of a parasite or preferentially expressed on cells infected with the parasite, wherein the parasite is Entamoeva histolytica, Valantidium coli, or Egleria Pauleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium bibox, Babesia microti, Trypanosoma brusei, Trypanosoma cruzi, Leishmania dono It is selected from the group consisting of Barney, Toxoplasma gondii, Nipostrongillus brasiliensis, Taenia crassicephalus, and Phrygia malai. Non-limiting examples of specific pathogen-related antibodies include, for example , HIV gp120, HIV CD4, hepatitis B glycoprotein L, hepatitis B glycoprotein M, hepatitis B glycoprotein S, hepatitis C E1, hepatitis C E2, hepatocytes -specific proteins, herpes simplex virus gB, cytomegalovirus gB, and HTLV envelope protein.

According to certain exemplary embodiments, the present invention includes bispecific antigen-binding molecules that specifically bind to CD3 and CD20. Such molecules may be referred to herein as, for example , "anti-CD3/anti-CD20" or "anti-CD3xCD20" or "CD3xCD20" bispecific molecules, or other similar terms.

As used herein, the term "CD20" refers to the human CD20 protein unless specified as being from a non-human species (eg, "mouse CD20", or "monkey CD20", etc.). Human CD20 protein has the amino acid sequence shown in SEQ ID NO: 1369.

As used herein, the expression "antigen-binding molecule", alone or in combination with one or more additional CDRs and/or framework regions (FRs), is one or more complementarity determinants that specifically bind a particular antigen. A protein, polypeptide or molecular complex comprising or consisting of regions (CDRs). In certain embodiments, the antigen-binding molecule is an antibody or fragment of an antibody, as those terms are defined elsewhere herein.

The expression “bispecific antigen-binding molecule” as used herein refers to a protein, polypeptide or molecular complex comprising at least a first antigen-binding domain and a second antigen-binding domain. Each antigen-binding domain in a bispecific antigen-binding molecule comprises one or more CDRs that specifically bind a particular antigen, either alone or in combination with one or more additional CDRs and/or FRs. In the context of the present invention, the first antigen-binding domain specifically binds a first antigen ( eg CD3) and the first antigen-binding domain binds a second distinct antigen ( eg CD20). bind specifically

In certain exemplary embodiments of the invention, the bispecific antigen-binding molecule is a bispecific antibody. Each antigen-binding domain of a bispecific antibody comprises a heavy chain variable domain (HCVR) and a light chain variable domain (LCVR). In the context of a bispecific antigen-binding molecule ( eg, a bispecific antibody) comprising first and second antigen-binding domains, the CDRs of the first antigen-binding domain may be denoted with the prefix "A1", The CDRs of the second antigen-binding domain may be designated with the prefix "A2". Thus, the CDRs of the first antigen-binding domain may be referred to herein as A1-HCDR1, A1-HCDR2, and A1-HCDR3; The CDRs of the second antigen-binding domain may be referred to herein as A2-HCDR1, A2-HCDR2, and A2-HCDR3.

The first antigen-binding domain and the second antigen-binding domain may be directly or indirectly linked to each other to form a bispecific antigen-binding molecule of the invention. Alternatively, the first antigen-binding domain and the second antigen-binding domain may each be linked to separate multimerization domains. Association of one multimerization domain with another multimerization domain enables association between the two antigen-binding domains, thereby forming a bispecific antigen-binding molecule. As used herein, a "multimerization domain" is any macromolecule, protein, polypeptide, peptide, or amino acid that has the ability to associate with a second multimerization domain of the same or similar structure or construct. For example, the multimerization domain can be a polypeptide comprising an immunoglobulin C _H 3 domain. Non-limiting examples of multimerizing components include the Fc portion of an immunoglobulin (including the C _H 2 -C _H 3 domain), eg, the Fc domain of an IgG selected from the isotypes IgG1, IgG2, IgG3, and IgG4, and It is any allotype within each isotype group.

A bispecific antigen-binding molecule of the invention will typically comprise two multimerization domains, eg two Fc domains, each separate part of a separate antibody heavy chain. The first and second multimerization domains can be of the same IgG isotype, eg , IgG1/IgG1, IgG2/IgG2, IgG4/IgG4. Alternatively, the first and second multimerization domains may be of different IgG isotypes, eg , IgG1/IgG2, IgG1/IgG4, IgG2/IgG4, etc.

In certain embodiments, the multimerization domain is an Fc fragment or amino acid sequence between 1 and about 200 amino acids in length containing one or more cysteine residues. In another embodiment, the multimerization domain is a cysteine residue, or a short cysteine-containing peptide. Other multimerization domains include peptides or polypeptides comprising or consisting of a leucine zipper, a helix-loop motif, or a coiled-coil motif.

Any bispecific antibody format or technology can be used to make the bispecific antigen-binding molecules of the present invention. For example, an antibody or fragment thereof having a first antigen-binding specificity may be coupled to one or more other molecular entities, eg, other antibodies or antibody fragments having a second antigen-binding specificity (e.g., chemical coupling, functionally linked (by genetic fusion, non-covalent association or otherwise)) to produce a bispecific antigen-binding molecule. Specific exemplary bispecific formats that may be used in the context of the present invention include, for example , scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadroma, knob- Into-Hole, Common Light Chain (e.g., Common Light Chain with Knob-Into-Hole, etc.), CrossMab, CrossFab, (SEED)body, Leucine Zipper, Duobody, IgG1/IgG2, Bifunctional Fab (DAF) -IgG, and Mab2 bispecific formats include, but are not limited to (for a review of these formats see, eg, Klein et al . 2012, mAbs 4:6, 1-11, and supra see references cited in).

In the context of a bispecific antigen-binding molecule of the invention, a multimerization domain, e.g., an Fc domain, has one or more amino acid changes ( e.g. , insertions, deletions, or substitutions) compared to the wild-type naturally occurring version of the Fc domain. ) may be included. For example, the present invention relates to a bispecific antigen comprising one or more modifications in an Fc domain resulting in a modified Fc domain having altered binding interactions (eg, enhanced or reduced) between Fc and FcRn. -Contains binding molecules. In one embodiment, the bispecific antigen-binding molecule comprises a modification within the _CH 2 or _CH 3 region, wherein the modification is performed in an acidic environment ( eg , at a pH ranging from about 5.5 to about 6.0, endo in some) increases the affinity of the Fc domain for FcRn. Non-limiting examples of such Fc modifications include, for example , position 250 ( eg , E or Q); 250 and 428 ( e.g. L or F); Modifications at 252 ( e.g. , L/Y/F/W or T), 254 ( e.g. , S or T), and 256 ( e.g. , S/R/Q/E/D or T) ; or a modification at positions 428 and/or 433 ( eg , L/R/S/P/Q or K) and/or 434 ( eg , H/F or Y); or a modification at position 250 and/or 428; or at positions 307 or 308 ( eg , 308F, V308F), and 434. In one embodiment, the variants include 428L ( eg , M428L) and 434S ( eg , N434S) strain; 428L, 259I ( e.g. V259I), and 308F ( e.g. V308F) variant; 433K ( eg H433K) and 434 ( eg 434Y) variants; 252, 254, and 256 ( e.g. , 252Y, 254T, and 256E) variants; 250Q and 428L variants ( eg , T250Q and M428L); and 307 and/or 308 variants ( eg , 308F or 308P).

The present invention also includes a bispecific antigen-binding molecule comprising a first C _H 3 domain and a second Ig C _H 3 domain, wherein the first and second Ig C _H 3 domains are at least one of each other. The amino acids are different, wherein the one or more amino acid differences reduce binding of the bispecific antibody to Protein A compared to a bispecific antibody lacking the amino acid difference. In one embodiment, the first Ig _CH 3 domain binds Protein A and the second Ig _CH 3 domain binds Protein A, eg, the H95R modification (by IMGT exon numbering; according to EU numbering). contains mutations that reduce or abolish H435R). The second C _H 3 may further comprise a Y96F modification (by IMGT; Y436F by EU). Additional modifications that may be found within the second C _H 3 include: D16E, L18M, N44S, K52N, V57M, and V82I (by IMGT; D356E, L358M, N384S, K392N, by EU) for IgG1 antibodies. V397M, and V422I); N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU) for IgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I by EU) for IgG4 antibodies.

In certain embodiments, an Fc domain may be a chimeric combinatorial Fc sequence derived from more than one immunoglobulin isotype. For example, a chimeric Fc domain may comprise part or all of a C _H 2 sequence derived from a human IgG1, human IgG2 or human IgG4 C _H 2 region, and a C _H 3 sequence derived from a human IgG1, human IgG2 or human IgG4. may include some or all of them. Additionally, a chimeric Fc domain may contain a chimeric hinge region. For example, a chimeric hinge may comprise an “upper hinge” sequence derived from a human IgG1, human IgG2 or human IgG4 hinge region combined with a “lower hinge” sequence derived from a human IgG1, human IgG2 or human IgG4 hinge region. can A specific example of a chimeric Fc domain that can be included in any of the antigen-binding molecules presented herein is from N-terminus to C-terminus: [IgG4 C _H 1] - [IgG4 upper hinge] - [IgG2 lower hinge] hinge] - [IgG4 CH2] - [IgG4 CH3]. Another example of a chimeric Fc domain that can be included in any of the antigen-binding molecules presented herein is N-terminus to C-terminus: [IgG1 C _H 1] - [IgG1 upper hinge] - [IgG2 lower hinge] hinge] - [IgG4 CH2] - [IgG1 CH3]. These and other examples of chimeric Fc domains that can be included in any of the antigen-binding molecules of the present invention are described in US Provisional Patent Application No. 61/759,578, filed February 1, 2013. Chimeric Fc domains with these general structural arrangements, and variants thereof, may have altered Fc receptor binding, which in turn affects Fc effector function.

sequence variants

Antibodies and bispecific antigen-binding molecules of the invention may contain one or more amino acid substitutions in the framework and/or CDR regions of the heavy and light chain variable domains, compared to the corresponding germline sequence from which the individual antigen-binding domains were derived; insertions and/or deletions. Such mutations can be readily identified, for example, by comparing the amino acid sequences disclosed herein to germline sequences available from public antibody sequence databases. An antigen-binding molecule of the invention may comprise an antigen-binding domain derived from any of the exemplary amino acid sequences disclosed herein, wherein one in one or more framework and/or CDR regions The above amino acids are relative to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to conservative amino acid substitutions of the corresponding germline residue(s). mutated (such sequence changes are collectively referred to herein as "germline mutations"). Starting with the heavy and light chain variable region sequences disclosed herein, one of ordinary skill in the art can readily generate a large number of antibodies and antigen-binding fragments comprising one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and/or CDR residues within the V _H and/or V _L domains are back mutated to residues found in the original germline sequence from which the original antigen-binding domain was derived. In another embodiment, only certain residues are mutated residues found, for example , within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or within CDR1, CDR2, or CDR3. Only the mutated residues are mutated back to the original germline sequence. In another embodiment, one or more of the framework and/or CDR residue(s) is mutated to the corresponding residue(s) in a different germline sequence ( i.e. , a germline sequence different from the germline sequence from which the antigen-binding domain was originally derived). do. In addition, an antibody of the invention may contain any combination of two or more germline mutations within the framework and/or CDR regions, e.g. , wherein certain individual residues are directed against corresponding residues in a particular germline sequence. While mutated, certain other residues that differ from the original germline sequence are either retained or mutated to corresponding residues in the different germline sequence. Once obtained, an antigen-binding domain containing one or more germline mutations may have one or more desirable properties, e.g., improved binding specificity, increased binding affinity, improved or enhanced antagonist or agonist biological properties (as the case may be). , reduced immunogenicity, and the like. Bispecific antigen-binding molecules comprising one or more antigen-binding domains obtained in this general manner are included within the present invention.

The invention also encompasses variants of any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein wherein one or both antigen-binding domains have one or more conservative substitutions. , which includes antigen-binding molecules. For example, the present invention relates to, for example , 10 or less, 8 or less, 6 or less, 4 or less, etc., for any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein. An antigen-binding molecule comprising an antigen-binding domain having an HCVR, LCVR, and/or CDR amino acid sequence with conservative amino acid substitutions of A "conservative amino acid substitution" is one that is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (eg, charge or hydrophobicity). In general, conservative amino acid substitutions will not substantially alter the functional properties of a protein. Examples of groups of amino acids having side chains with similar chemical properties include (1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; (2) aliphatic-hydroxyl side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartate and glutamate, and (7) sulfur-containing side chains: cysteine and methionine. Preferred conservative amino acid substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. Alternatively, conservative replacements are described in Gonnet et al. (1992) Science 256: 1443-1445, is any change with a positive value in the PAM250 log-likelihood matrix. A “moderately conservative” replacement is any change with a non-negative value in the PAM250 log-likelihood matrix.

The invention also provides an antigen-binding domain comprising an antigen-binding domain having an HCVR, LCVR, and/or CDR amino acid sequence that is substantially identical to any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein. -Contains binding molecules. The term "substantial identity" or "substantially identical" when referring to amino acid sequences means that the two amino acid sequences are 95% or more of the sequences if they are optimally aligned, for example by the programs GAP or BESTFIT using default gap weights. It means sharing identity, even more preferably at least 98% or at least 99% sequence identity. Preferably, residue positions that are not identical differ by conservative amino acid substitutions. When two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity can be adjusted upward to correct for the conservative nature of the substitutions. Means for making this adjustment are well known to those skilled in the art. See, eg , Pearson (1994) Methods Mol. Biol. 24: 307-331.

Sequence similarity for polypeptides, also referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software uses measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions, to match similar sequences. For example, GCG software can detect sequence homology or sequence identity between closely related polypeptides, eg, homologous polypeptides from different species of organisms, or between a wild-type protein and its muteins. It contains programs that can be used with default parameters to measure, eg Gap and Bestfit. For example , see GCG version 6.1. Polypeptide sequences can also be compared using FASTA using default or recommended parameters, a program in GCG version 6.1. FASTA (eg, FASTA2 and FASTA3) provides alignment and percent sequence identity of the region of highest overlap between query and search sequences (Pearson (2000) supra). Another preferred algorithm for comparing sequences of the present invention to a database containing a large number of sequences from different organisms is the computer program BLAST, particularly BLASTP or TBLASTN, using default parameters. See, for example , Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389-402 ] .

pH-dependent binding

The present invention includes anti-CD3 antibodies, and anti-CD3/anti-CD20 bispecific antigen-binding molecules with pH-dependent binding characteristics. For example, an anti-CD3 antibody of the present invention may exhibit reduced binding to CD3 at acidic pH compared to neutral pH. Alternatively, anti-CD3 antibodies of the present invention may exhibit enhanced binding to CD3 at acidic pH as compared to neutral pH. The expression "acidic pH" is less than about 6.2, for example , 6.0, 5.95, 5,9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2 , 5.15, 5.1, 5.05, 5.0, or less. As used herein, the expression "neutral pH" means a pH of about 7.0 to about 7.4. The expression “neutral pH” includes pH values of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.

In certain instances, “reduced binding to … at acidic pH as compared to neutral pH” is the _ratio of the KD value of antibody binding to antigen at acidic pH to the KD value of antibody binding to antigen at neutral pH _. Expressed in terms of ratios (or vice versa). For example, an antibody or antigen-binding fragment thereof may, for the purposes of the present invention, bind to CD3 at an acidic pH relative to neutral pH if the antibody or antigen-binding fragment thereof exhibits an acidic/neutral K _D ratio of at least about 3.0. reduced binding to". In certain exemplary embodiments, the acidic/neutral K _D ratio for an antibody or antigen-binding fragment of the invention is about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5 , 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0. 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0 or more.

Antibodies with pH-dependent binding properties can be obtained, for example , by screening a population of antibodies for reduced (or improved) binding to a particular antigen at acidic pH as compared to neutral pH. Additionally, modification of the antigen-binding domain at the amino acid level can yield antibodies with pH-dependent characteristics. For example, by substituting one or more amino acids of an antigen-binding domain (eg, within a CDR) with a histidine residue, an antibody with reduced antigen-binding at acidic pH compared to neutral pH can be obtained.

Antibodies containing Fc variants

According to certain embodiments of the invention, an anti-CD3 antibody comprising an Fc domain comprising one or more mutations that enhance or decrease antibody binding to the FcRn receptor at acidic pH, eg, as compared to neutral pH, and Anti-CD3/anti-CD20 bispecific antigen-binding molecules are provided. For example, the present invention includes antibodies comprising a mutation in the _CH 2 or _CH 3 region of an Fc domain, wherein the mutation(s) is present in an acidic environment ( eg , at a pH between about 5.5 and 5.5). increases the affinity of the Fc domain for FcRn (in endosomes in the range of about 6.0). Such mutations may result in an increase in the serum half-life of the antibody when administered to animals. Non-limiting examples of such Fc modifications include, for example , position 250 (eg, E or Q); 250 and 428 (eg L or F); Modifications in 252 (e.g. L/Y/F/W or T), 254 (e.g. S or T), and 256 (e.g. S/R/Q/E/D or T) ; or a modification at positions 428 and/or 433 (eg, H/L/R/S/P/Q or K) and/or 434 ( eg , H/F or Y); or a modification at position 250 and/or 428; or at positions 307 or 308 ( eg , 308F, V308F), and 434. In one embodiment, the variants include 428L ( eg , M428L) and 434S ( eg , N434S) strain; 428L, 259I ( e.g. V259I), and 308F ( e.g. V308F) variant; 433K ( eg H433K) and 434 ( eg 434Y) variants; 252, 254, and 256 ( e.g. , 252Y, 254T, and 256E) variants; 250Q and 428L variants ( eg , T250Q and M428L); and 307 and/or 308 variants ( eg , 308F or 308P).

For example, the present invention includes 250Q and 248L ( eg , T250Q and M248L); 252Y, 254T and 256E ( eg , M252Y, S254T and T256E); 428L and 434S ( eg , M428L and N434S); and an Fc domain comprising at least one pair or group of mutations selected from the group consisting of 433K and 434F ( eg , H433K and N434F), and an anti-CD3/anti-CD20 bispecific Including migratory antigen-binding molecules. All possible combinations of the above Fc domain mutations, and other mutations within the antibody variable domains disclosed herein, are contemplated within the scope of the present invention.

Biological Characteristics of Antibodies and Bispecific Antigen-Binding Molecules

The present invention includes antibodies and antigen-binding fragments thereof that bind to human CD3 and induce T cell proliferation. For example, the present invention provides an in vitro T cell proliferation assay ( eg, of Jurkat cells or human PBMCs in the presence of an anti-CD3 antibody) using an assay format, eg , as defined in Example 4 herein. assays proliferation), or an anti-CD3 antibody that induces human T cell proliferation with an EC ₅₀ value of less than about 0.33 pM as measured by a substantially similar assay. In certain embodiments, an antibody or antigen-binding fragment of the invention, as measured by an in vitro T cell proliferation assay using, eg, an assay format as defined in Example 4, or a substantially similar assay, is about Human T cell proliferation ( e.g., with an EC ₅₀ value of less than about 0.32 pM, less than about 0.31 pM, less than about 0.30 pM, less than about 0.28 pM, less than about 0.26 pM, less than about 0.24 pM, less than about 0.22 pM, or less than about 0.20 pM) eg , Jurkat cell proliferation and/or PBMC proliferation).

The present invention also includes antibodies and antigen-binding fragments thereof that bind to human CD3 and induce T cell-mediated killing of tumor cells. For example , the present invention provides an in vitro T cell-mediated tumor cell killing assay ( eg, in the presence of an anti-CD3 antibody) using an assay format as defined in Example 6 herein. Assessing the extent of U937 tumor cell killing by PBMC), or an anti-CD3 antibody that induces T cell-mediated killing of tumor cells with an EC ₅₀ value of less than about 2.3 pM as measured in a substantially similar assay. do. In certain embodiments, an antibody or antigen-binding fragment of the invention is used in an in vitro T cell-mediated tumor cell killing assay, e.g. , using an assay format as defined in Example 6 herein, or a substantially similar Less than about 2.3 pM, less than about 2.2 pM, less than about 2.1 pM, less than about 2.0 pM, less than about 1.8 pM, less than about 1.6 pM, less than about 1.4 pM, less than about 1.2 pM, less than about 1.0 pM as measured by assay; Induce T cell-mediated tumor cell killing ( eg, PBMC-mediated killing of U937 cells) with an EC ₅₀ value of less than about 0.8 pM, less than about 0.6 pM, or less than about 0.5 pM.

The present invention includes antibodies and antigen-binding fragments thereof that bind human CD3 with high affinity. The present invention also includes antibodies and antigen-binding fragments thereof that bind human CD3 with moderate or low affinity, depending on the therapeutic context and the particular targeting properties desired. For example, in the context of a bispecific antigen-binding molecule in which one arm binds CD3 and the other arm binds a target antigen ( eg , CD20), with respect to the target antigen-binding arm, the target antigen has a high degree of binding. It may be desirable to bind with affinity, whereas the anti-CD3 arm binds CD3 with only moderate or low affinity. In this way, preferential targeting of the antigen-binding molecule to cells expressing the target antigen can be achieved while avoiding generic/non-targeted CD3 binding and consequent detrimental side effects associated therewith.

According to certain embodiments, the invention provides, for example , when measured by surface plasmon resonance using an assay format as defined in Example 3 herein ( eg , a mAb-capture or antigen-capture format) , antibodies and antigen-binding fragments of antibodies that bind human CD3 with a K _D of less than about 15 nM (eg, at 25° C.). In certain embodiments, an antibody or antigen-binding fragment of the invention is, for example , as measured by surface plasmon resonance using an assay format as defined in Example 3 herein, or a substantially similar assay, of about Less than 5 nM, less than about 2 nM, less than about 1 nM, less than about 800 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 180 pM, less than about 160 pM, less than about 140 pM, less than about 120 pM , with a K _D of less than about 100 pM, less than about 80 pM, less than about 60 pM, less than about 40 pM, less than about 20 pM, or less than about 10 pM.

In addition, the present invention provides a time greater than about 10 minutes, e.g., as measured by surface plasmon resonance at 25°C or 37°C using an assay format as defined in Example 3 herein, or a substantially similar assay. It includes antibodies and antigen-binding fragments thereof that bind CD3 with a dissociation half-life (t½) of. In certain embodiments, an antibody or antigen-binding fragment of the invention is tested at 25° C. using an assay format ( eg , mAb-capture or antigen-capture format) as defined in Example 3 herein. or greater than about 20 minutes, greater than about 30 minutes, greater than about 40 minutes, greater than about 50 minutes, greater than about 60 minutes, greater than about 70 minutes, as measured by surface plasmon resonance at 37°C, or a substantially similar assay; greater than about 80 minutes, greater than about 90 minutes, greater than about 100 minutes, greater than about 200 minutes, greater than about 300 minutes, greater than about 400 minutes, greater than about 500 minutes, greater than about 600 minutes, greater than about 700 minutes, greater than about 800 minutes; Binds to CD3 with a t½ greater than about 900 minutes, greater than about 1000 minutes, or greater than about 1200 minutes.

The present invention includes bispecific antigen-binding molecules ( eg, bispecific antibodies) capable of binding to human CD3 and human CD20 simultaneously. According to certain embodiments, the bispecific antigen-binding molecules of the invention specifically interact with cells expressing CD3 and/or CD20. The extent to which a bispecific antigen-binding molecule binds to cells expressing CD3 and/or CD20 can be assessed by fluorescence activated cell sorting (FACS) as shown in Example 8 herein. For example, the present invention provides a human T-cell line expressing CD3 but not CD20 ( eg Jurkat), a human B-cell line expressing CD20 but not CD3 ( eg Raji), and/or bispecific antigen-binding molecules that specifically bind to primate T-cells ( eg , cynomolgus peripheral blood mononuclear cells [PBMC]). The present invention provides the aforementioned cells and cell lines with an EC ₅₀ value of about 9.0x10 ^-6 to about 2.0x10 ^-9 , or less, as measured using the FACS assay set forth in Example 8 or a substantially similar assay. It includes bispecific antigen-binding molecules that bind to any of these.

The present invention also includes anti-CD3/anti-CD20 bispecific antigen-binding molecules that bind to CD3-expressing human T-cells ( eg , Jurkat) with an EC ₅₀ value of 1.0 pM to 1000 nM. In certain embodiments, the anti-CD3/anti-CD20 bispecific antigen-binding molecule binds CD3-expressing human T-cells with an EC ₅₀ value between 1 nM and 60 nM. For example, the present invention, about 1pM, about 10pM, about 100pM, about 500pM, about 1nM, about 2nM, about 5nM, about 10nM, about 20nM, about 30nM, about 40nM, about 50nM, about 60nM, about 70nM, binds to CD3-expressing human T-cells ( eg , Jurkat) with an EC ₅₀ value of about 80 nM, about 90 nM, about 100 nM, about 200 nM, about 300 nM, about 500 nM, about 800 nM, about 1000 nM, or less; Anti-CD3/anti-CD20 bispecific antigen-binding molecules.

In addition, the present invention is directed to (a) inducing PBMC proliferation in vitro ( see, eg , Example 9 herein); (b) T-cell activation, induction of IFN-gamma release and CD25 up-regulation in human whole blood ( see, eg , Example 10 herein); (c) induction of T-cell mediated cytotoxicity against anti-CD20-resistant cell lines ( see, eg , Example 11 herein); (d) inducing cytotoxicity to human B-cells ( eg , Raji; see, eg , Example 13 herein); (e) B-cell depletion ( eg , CD19+ B-cells) in mice reconstituted with human immune cells (see, eg, Example 14 herein; and (f) B-cells in mouse xenografts. reduction in tumor volume ( eg , Raji tumor volume) ( see, eg, Example 15). .

The present invention includes anti-CD3/anti-CD20 bispecific antigen-binding molecules capable of depleting B cells in a subject ( see eg Example 16). For example, according to certain embodiments, an anti-CD3/anti-CD20 bispecific antigen-binding molecule is provided, wherein the dose to a subject ( e.g. , about 0.1 mg/kg, about 0.08 mg/kg, about A single administration of a bispecific antigen-binding molecule (at a dose of 0.06 mg/kg, about 0.04 mg/kg, about 0.04 mg/kg, about 0.02 mg/kg, about 0.01 mg/kg, or less) can cause a subject to to below detectable levels in the number of B cells ( eg, in a blood sample drawn from the subject). In certain embodiments, a single administration of the anti-CD3/anti-CD20 bispecific antigen-binding molecule at a dose of about 0.1 mg/kg is about 7 days, about 6 days of administration of the bispecific antigen-binding molecule to the subject. , a decrease in the number of B cells in the subject to less than a detectable level by about 5 days, about 4 days, about 3 days, about 2 days, or about 1 day. According to certain embodiments, a single administration of an anti-CD3/anti-CD20 bispecific antigen-binding molecule of the invention at a dose of about 0.01 mg/kg is administered at least about 7 days, 8 days, 9 days, 10 days after administration. Days 11, 12, 13, 14, 15, 16, 17, or longer, allow the number of B-cells to remain below detectable levels. As used herein, the expression “below detectable level” refers to blood samples drawn from a subject using a standard B-cell detection assay, such as the FACS assay for B-cell markers set forth in Example 16 herein. It means that there are no B cells that can be detected directly or indirectly.

In a related embodiment, the number of B-cells per microliter of blood drawn from the subject from about 1 day to about 28 days after administration of a single dose of about 0.01 mg/kg of the antigen-binding molecule to the subject is the number of B-cells taken from the subject prior to administration. An anti-CD3/anti-CD20 bispecific antigen-binding molecule that is less than 25% of the number of B-cells per microliter of blood is provided. In certain other embodiments, the number of B-cells per microliter of blood drawn from the subject from about 1 day to about 56 days after administration of a single dose of about 0.01 mg/kg of an antigen-binding molecule to the subject is reduced from the subject prior to administration. An anti-CD3/anti-CD20 bispecific antigen-binding molecule is provided that is less than 50% of the number of B-cells per microliter of blood drawn.

The present invention also provides anti-CD3/anti-CD20 bispecific antigen-binding molecules that, when administered to a subject, do not cause more than a transient decrease in T cells. For example, when administered to a subject at a dose of about 0.01 mg/kg, it reduces the number of T cells 1 day after administration, but at a later time point ( eg, about 2 days, 7 days, 14 days, 28 days after administration) day, 42, 56 or later), the number of T cells per microliter of blood is brought back. For example, the present invention relates to the number of T cells per microliter of blood drawn from a subject between about 14 days and about 56 days after administration of the antigen-binding molecule at a dose of about 0.01 mg/kg to the subject, of the bispecific antigen-binding molecule. Provided are anti-CD3/anti-CD20 bispecific antigen-binding molecules that are equal to or greater than the number of T cells per microliter of blood drawn from the subject prior to administration.

Epitope mapping and related techniques

The epitope on CD3 to which the antigen-binding molecule of the present invention binds is three or more of the CD3 protein ( eg , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more) amino acids. Alternatively, an epitope may consist of a plurality of non-contiguous amino acids (or amino acid sequences) of CD3. Antibodies of the invention may interact with amino acids contained within a single CD3 chain ( eg , CD3-epsilon, CD3-delta or CD3-gamma), or may interact with amino acids on two or more different CD3 chains. As used herein, the term "epitope" refers to an antigenic determinant that interacts with a specific antigen binding site within the variable region of an antibody molecule, known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different regions on an antigen and may have different biological effects. Epitopes can be conformational or linear. Conformational epitopes are created by spatially juxtaposing amino acids from different segments of a linear polypeptide chain. A linear epitope is one produced by contiguous amino acid residues within a polypeptide chain. In certain circumstances, an epitope may include a moiety of a saccharide, phosphoryl group, or sulfonyl group on an antigen.

A variety of techniques known to those skilled in the art can be used to determine whether the antigen-binding domain of an antibody “interacts with one or more amino acids” in a polypeptide or protein. Exemplary techniques include, for example , routine cross-blocking assays, such as those described in Antibodies , Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., NY), alanine scanning mutation analysis, peptide blot analysis (Reineke, 2004, Methods Mol Biol 248:443-463), and peptide cleavage analysis. In addition, methods such as epitope excision, epitope extraction, and chemical modification of antigens can be used (Tomer, 2000, Protein Science 9:487-496). Another method that can be used to identify amino acids within a polypeptide with which the antigen-binding domain of an antibody interacts is hydrogen/deuterium exchange detected by mass spectrometry. Generally, the hydrogen/deuterium exchange method involves deuterium-labeling a protein of interest followed by binding an antibody to the deuterium-labeled protein. The protein/antibody complex is then transferred to water, allowing hydrogen-deuterium exchange to occur at all residues except those protected by the antibody, which remain deuterium-labeled. After dissociation of the antibody, the target protein is subjected to protease cleavage and mass spectrometric analysis, revealing deuterium-labeled residues corresponding to the specific amino acids with which the antibody interacts. See, eg , Ehring (1999) Analytical Biochemistry 267(2):252-259; Engen and Smith (2001) Anal. Chem. 73 :256A-265A ] . Additionally, X-ray crystallography of antigen/antibody complexes can also be used for epitope mapping purposes.

The present invention provides anti-antibodies that bind to the same epitope as any of the specific exemplary antibodies described herein ( eg, antibodies comprising any of the amino acid sequences as set forth in Table 1 herein). Further includes a CD3 antibody. Similarly, the present invention also relates to any of the specific exemplary antibodies described herein for binding to CD3 ( eg, antibodies comprising any of the amino acid sequences as set forth in Table 1 herein). Anti-CD3 antibody that competes with the antibody).

In addition, the present invention is a bispecific antigen-binding molecule comprising a first antigen-binding domain that specifically binds to human CD3 and a second antigen-binding domain that specifically binds to human CD20, wherein the first antigen - the binding domain binds to the same epitope on CD3 as any of the specific exemplary CD3-specific antigen-binding domains described herein, and/or the second antigen-binding domain, on CD20, It includes a bispecific antigen-binding molecule that binds to the same epitope as any of the specific exemplary CD20-specific antigen-binding domains described in .

Similarly, the present invention also provides a bispecific antigen-binding molecule comprising a first antigen-binding domain that specifically binds human CD3, and a second antigen-binding domain that specifically binds human CD20, wherein the The first antigen-binding domain competes with any of the specific exemplary CD3-specific antigen-binding domains described herein for binding to CD3, and/or the second antigen-binding domain binds to CD20. A bispecific antigen-binding molecule that competes for binding with any of the specific exemplary CD20-specific antigen-binding domains described herein.

One skilled in the art can determine whether a particular antigen-binding molecule ( eg , antibody) or antigen-binding domain thereof binds to the same epitope as a reference antigen-binding molecule of the invention, using routine methods known in the art. , or competes for binding with the reference antigen-binding molecule. For example, to determine whether a test antibody binds to the same epitope as a reference bispecific antigen-binding molecule of the invention, the reference bispecific antigen-binding molecule is allowed to bind to the CD3 protein (or CD2 protein). The ability of the test antibody to bind to the CD3 (or CD20) molecule is then evaluated. If the test antibody is capable of binding to CD3 (or CD20) following saturation binding with the reference bispecific antigen-binding molecule, then the test antibody binds to a different epitope of CD3 (or CD20) than the reference bispecific antigen-binding molecule It can be concluded that On the other hand, if the test antibody is unable to bind to the CD3 (or CD20) molecule following saturating binding with the reference bispecific antigen-binding molecule, at this time, the test antibody is inhibited by the reference bispecific antigen-binding molecule of the present invention. It can bind to the same epitope of CD3 (or CD20) as the bound epitope. Then, to determine whether the observed lack of binding of the test antibody is in fact due to binding to the same epitope as the reference bispecific antigen-binding molecule, or whether steric blockade (or other phenomena) is responsible for the observed lack of binding For this purpose, additional routine experiments ( eg , peptide mutagenesis and binding assays) can be performed. Experiments of this kind can be performed using ELISA, RIA, Biacore, flow cytometry or any other quantitative or qualitative antibody-binding assay available in the art. According to certain embodiments of the present invention, for example , a 1-, 5-, 10-, 20- or 100-fold excess of one antigen-binding protein is used in a competitive binding assay (see, e.g., Junghans et al. al., Cancer Res. 1990:50:1495-1502), when inhibiting the binding of another antibody by 50% or more, but preferably by 75%, 90% or even 99%, two antigen-binding Proteins bind to the same (or overlapping) epitopes. Alternatively, two antigen-binding proteins bind to the same epitope if essentially all amino acid mutations in an antigen that reduce or eliminate binding of one antigen-binding protein reduce or eliminate binding of the other antigen-binding protein. It is thought to do Two antigen-binding proteins have "overlapping epitopes" if only a subset of amino acid mutations that reduce or eliminate binding of one antigen-binding protein reduce or eliminate binding of the other antigen-binding protein. It is thought to be

To determine whether an antibody competes for binding with a reference antigen-binding molecule, the above-described binding method is performed in two orientations: In the first orientation, the reference antibody is subjected to saturating conditions with the CD3 protein (or CD20 protein). , and then the binding of the test antibody to the CD3 (or CD20) molecule is assessed. In a second orientation, a test antibody is allowed to bind to a CD3 (or CD20) molecule under saturating conditions, and then the binding of the reference antigen-binding molecule to the CD3 (or CD20) molecule is assessed. In both of these orientations, if only the first (saturated) antigen-binding molecule is capable of binding the CD3 (or CD20) molecule, then the test antibody and the reference antigen-binding molecule are required to bind CD3 (or CD20). It is concluded that competition As will be appreciated by those of ordinary skill in the art, an antibody that competes for binding with a reference antigen-binding molecule may not necessarily bind to the same epitope as the reference antibody, but may bind to overlapping or adjacent epitopes, thereby Binding of the reference antibody can be sterically blocked.

Preparation of antigen-binding domains and construction of bispecific molecules

Antigen-binding domains specific for a particular antigen can be prepared by any antibody generating technique known in the art. Once obtained, two different HA-binding domains specific for two different antigens ( eg , CD3 and CD20) can be used to prepare the bispecific antigen-binding molecules of the present invention using routine methods. may be suitably arranged relative to each other. (A discussion of exemplary bispecific antibody formats that can be used to construct the bispecific antigen-binding molecules of the invention is provided elsewhere herein). In certain embodiments, one or more of the individual components ( eg , heavy and light chains) of the multispecific antigen-binding molecules of the invention are derived from chimeric, humanized or fully human antibodies. Methods for preparing such antibodies are well known in the art. For example, one or more of the heavy and/or light chains of a bispecific antigen-binding molecule of the invention can be made using VELOIMMUNE™ technology. Using VELOIMMUNE™ technology (or any other human antibody generation technology), high affinity chimeric antibodies with human variable regions and mouse constant regions against a specific antigen ( eg , CD3 or CD20) are first isolated . Antibodies are characterized and selected for desired properties including affinity, selectivity, epitope, and the like. Replacement of the mouse constant region with a desired human constant region results in fully human heavy and/or light chains that can be incorporated into the bispecific antigen-binding molecules of the present invention.

Genetically engineered animals can be used to produce human bispecific antigen-binding molecules. For example, genetically modified mice that are unable to rearrange and express endogenous mouse immunoglobulin light chain variable sequences can be used, wherein the mouse is a human operably linked to a mouse kappa constant gene at the endogenous mouse kappa locus. Expresses only one or two human light chain variable domains encoded by immunoglobulin sequences. Using these genetically modified mice, a fully human bispecific antigen-binding molecule comprising two different heavy chains in association with the same light chain comprising a variable domain derived from one of two different human light chain variable region gene segments. can be manufactured. (See, eg, US 2011/0195454 for a detailed discussion of such engineered mice and their use to make bispecific antigen-binding molecules).

bioequivalence

The present invention includes antigen-binding molecules having amino acid sequences that vary from the sequences of exemplary molecules disclosed herein but retain the ability to bind CD3 and/or CD20. Such variant molecules may contain one or more additions, deletions, or substitutions of amino acids when compared to the parent sequence, but exhibit biological activities that are essentially equivalent to those of the described bispecific antigen-binding molecules.

The present invention includes antigen-binding molecules that are bioequivalent to any of the exemplary antigen-binding molecules set forth herein. Note that two antigen-binding proteins, or antibodies, are administered in identical molar doses, e.g., in a single dose or in multiple doses, under experimental conditions in which they are pharmaceutically equivalent, or whose rates and extent of absorption are similar. Pharmaceutical substitutes that do not exhibit significant differences are considered bioequivalent. Several antigen-binding proteins will be considered equivalent or pharmaceutical substitutes if they are equivalent in terms of their extent of uptake but not equivalent in their rate of uptake, and this difference in uptake rate is intentional and labeling. , may still be considered bioequivalent as it is not essential to obtaining effective drug concentrations in the body, eg in chronic use, and is not considered medically significant for the particular drug product studied.

In one embodiment, two antigen-binding proteins are bioequivalent if there are no clinically meaningful differences in their safety, purity, and potency.

In one embodiment, the two antigen-binding proteins have a clinically significant change, or decrease, in immunogenicity compared to a therapy in which the patient was continued without switching between the reference product and the biological product. Bioequivalence is when it can be switched between the reference product and the biological product one or more times without an expected increase in the risk of side effects including improved efficacy.

In one embodiment, two antigen-binding proteins are bioequivalent if they both act by a common mechanism or mechanisms for the condition or conditions of use to the extent that the mechanism of action is known.

Bioequivalence can be demonstrated by in vivo and in vitro methods. Bioequivalence measures include, for example, (a) an in vivo test in humans or other mammals in which the concentration of the antibody or its metabolite is measured in blood, plasma, serum or other biological fluid as a function of time; (b) an in vitro test that correlates with and is sufficiently predictive of human in vivo bioavailability data; (c) an in vivo test in humans or other mammals, where appropriate acute pharmacological effects of the antibody (or its target) are determined as a function of time; and (d) well-controlled clinical trials that establish the safety, efficacy, or bioavailability or bioequivalence of the antigen-binding protein.

Bioequivalent variants of exemplary bispecific antigen-binding molecules provided herein include, for example, various substitutions of terminal or internal residues or sequences that are not required for biological activity or terminal or internal residues or sequences that are not required for biological activity. It can be constructed by making a deletion of . For example, cysteine residues not essential for biological activity can be deleted or replaced with other amino acids to prevent formation of unnecessary or inaccurate intramolecular disulfide bridges upon renaturation. In another aspect, a bioequivalent antigen-binding protein disclosed herein comprises an amino acid change that alters the glycosylation properties of an exemplary bispecific antigen-binding molecule, eg, a mutation that eliminates or deletes glycosylation. variants of exemplary bispecific antigen-binding molecules.

Species selectivity and species cross-reactivity

According to certain embodiments of the present invention, antigen-binding molecules that bind human CD3 but not CD3 from other species are provided. Also provided are antigen-binding molecules that bind human CD20 but not CD20 from other species. The present invention also relates to antigen-binding molecules that bind to human CD3 and to CD3 from one or more non-human species; and/or antigen-binding molecules that bind to human CD20 and to CD20 from one or more non-human species.

According to certain exemplary embodiments of the invention, binds to human CD3 and/or human CD20, optionally mouse, rat, guinea pig, hamster, gerbil, pig, cat, dog, rabbit, goat, sheep , bovine, equine, camel, cynomolgus, marmoset, rhesus or chimpanzee antigen-binding molecules that may or may not bind to one or more of CD3 and/or CD20 are provided. For example, in certain exemplary embodiments of the invention, a first antigen-binding domain that binds human CD3 and cynomolgus CD3, and a second antigen-binding domain that specifically binds human CD20. Bispecific antigen-binding molecules are provided.

immune conjugate

The present invention includes antigen-binding molecules conjugated to therapeutic moieties (“immunoconjugates”) such as cytotoxins, chemotherapeutic drugs, immunosuppressants or radioactive isotopes. A cytotoxic agent includes any agent that is detrimental to cells. Examples of suitable cytotoxic and chemotherapeutic agents for forming immune conjugates are known in the art (see for example WO 05/103081).

Therapeutic formulation and administration

The present invention provides pharmaceutical compositions comprising the antigen-binding molecules of the present invention. The pharmaceutical compositions of the present invention are formulated with suitable carriers, excipients, and other agents that provide improved transport, delivery, and tolerability, and the like. A number of suitable formulations can be found in prescriptions known to all pharmacists (Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA). These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (e.g. LIPOFECTIN™, Life Technologies, Carlsbad , CA), DNA conjugates, anhydrous adsorbent pastes, oil-in-water and water-in-oil emulsions, emulsion carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax included Also, see Powell et al. See "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311.

The dose of the antigen-binding molecule administered to a patient may vary depending on the patient's age and physique, target disease, condition, route of administration, and the like. Preferred doses are usually calculated according to body weight or body surface area. When the bispecific antigen-binding molecule of the present invention is used for therapeutic purposes in adult patients, the bispecific antigen-binding molecule of the present invention is usually administered at about 0.01 to about 20 mg/kg body weight, more preferably about 0.02 to about 20 mg/kg of body weight. Intravenous administration in a single dose of about 7, about 0.03 to about 5, or about 0.05 to about 3 mg/kg body weight may be advantageous. Depending on the severity of the condition, the frequency and duration of treatment may be adjusted. Effective doses and schedules for administering bispecific antigen-binding molecules can be determined empirically; For example, patient progress may be monitored with periodic assessments and dose adjustments may be made accordingly. In addition, interspecies scaling of doses may be performed using methods well known in the art [ eg , Mordenti et al. , 1991, Pharmaceut. Res. 8 :1351].

Various delivery systems such as liposomes, microparticles, encapsulation of microcapsules, recombinant cells capable of expressing mutant viruses, receptor mediated endocytosis, etc. are known and can be used to administer the pharmaceutical composition of the present invention. can be [eg, Wu et al., 1987, J. Biol. Chem. 262:4429-4432]. Methods of introduction include, but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural and oral routes. The composition is administered by any convenient route, eg, by infusion or bolus injection, by absorption through an epithelial or mucocutaneous lining (eg, oral mucosa, rectal and intestinal mucosa, etc.) It can be administered with other biologically active agents. Administration may be systemic or local.

The pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously using a standard needle and syringe. Also, with respect to subcutaneous delivery, a pen delivery device is readily adapted to deliver the pharmaceutical composition of the present invention. Such pen delivery devices may be reusable or disposable. Reusable pen delivery devices generally utilize a replaceable cartridge containing a pharmaceutical composition. Once all of the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be discarded and replaced easily with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In the case of disposable pen delivery devices, there are no replaceable cartridges. Rather, the disposable pen delivery device is pre-filled with a pharmaceutical composition contained in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

A number of reusable pens and autoinjector delivery devices are employed for subcutaneous delivery of the pharmaceutical compositions of the present invention. Examples include the AUTOPEN™ (manufactured by Owen Mumford, Inc., Woodstock, UK), the DISETRONIC™ pen (manufactured by Disetronic Medical Systems, Bergdorf, Switzerland), the HUMALOG MIX 75/25™ pen, to name just a few. , HUMALOG™ PEN, HUMALIN 70/30™ PEN (manufacturer: Eli Lilly and Co., Indianapolis, IN, USA), NOVOPEN™ I, II and III (manufacturer: Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ ( Manufactured by: Novo Nordisk, Copenhagen, Denmark), BD™ pen (manufactured by Becton Dickinson, Franklin Lakes, NJ, USA), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™ and OPTICLIK™ (manufactured by sanofi-aventis, Frankfurt, Germany) ) are included, but are not limited thereto. Examples of disposable pen delivery devices applied for subcutaneous delivery of the pharmaceutical composition of the present invention include the SOLOSTAR™ pen (manufacturer: sanofi-aventis), FLEXPEN™ (manufacturer: Novo Nordisk), and KWIKPEN™, to name just a few. (manufacturer: Eli Lilly), SURECLICK™ autoinjector (Amgen, Thousand Oaks, CA, USA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, L.P.) and HUMIRA™ pens (Abbot Park, IL, USA) of Abbott Labs), but is not limited thereto.

In certain circumstances, the pharmaceutical composition may be delivered as a controlled release system. In one embodiment, a pump may be used. Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201]. In other embodiments, polymeric materials may be used; See Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In another embodiment, only a fraction of the systemic dose may be required by placing the controlled release system in the vicinity of the target of the composition [ eg , Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, p. 115-138]. Other controlled release systems are discussed in a review of the literature (Langer, 1990, Science 249:1527-1533).

Injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injection, infusion and the like. These injectable formulations can be prepared by publicly known methods. For example, injectable preparations can be prepared, for example , by dissolving, suspending, or emulsifying the above-described antibody or salt thereof in a sterile aqueous medium or an oleaginous medium commonly used for injection. Aqueous media for injection include, for example, physiological saline, isotonic solutions containing glucose and other adjuvants, and the like, which are formulated with appropriate solubilizers such as alcohols (eg ethanol), polyhydric alcohols (eg , propylene glycol, polyethylene glycol), nonionic surfactants [eg, polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)] and the like. As the oily medium, for example, sesame oil, soybean oil and the like are used, which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol and the like. The injectable preparation thus prepared is preferably filled into an appropriate ampoule.

Advantageously, the pharmaceutical composition for oral or parenteral use described above is prepared in unit dose dosage form suitable for adjusting the dosage of the active ingredient. Such dosage forms in unit doses include, for example, tablets, pills, capsules, injections (ampoules), suppositories and the like. The content of the aforementioned antibody is generally about 5 to about 500 mg per dosage form in unit dose; In particular, it is preferable to contain about 5 to about 100 mg of the above-mentioned antibody in the case of an injectable form and about 10 to about 250 mg in the case of other dosage forms.

Therapeutic Uses of Antigen-Binding Molecules

The present invention comprises administering to a subject in need thereof a therapeutic composition comprising an anti-CD3 antibody or bispecific antigen-binding molecule that specifically binds CD3 and a target antigen (eg, CD20). to do, including how to A therapeutic composition may include any of the antibodies or bispecific antigen-binding molecules as disclosed herein and a pharmaceutically acceptable carrier or diluent. As used herein, the expression "subject in need of treatment" refers to a human or non-human or non-human who exhibits one or more symptoms or indicators of cancer, or who may benefit from inhibition or reduction of CD20 activity, or depletion of CD20+ B cells. -means a human animal (eg, a subject expressing a tumor or suffering from any of the cancers mentioned hereinbelow).

Antibodies and bispecific antigen-binding molecules (and therapeutic compositions comprising them) of the invention are useful, inter alia, for the treatment of any disease or disorder for which stimulation, activation and/or targeting of an immune response may be beneficial. In particular, the anti-CD3/anti-CD20 bispecific antigen-binding molecules of the present invention are used for the treatment, prevention and/or treatment of any disease or disorder associated with or mediated by CD20 expression or activity or proliferation of CD20+ B cells. can be used for improvement. The mechanism of action by which the therapeutic methods of the invention are achieved may be, for example, by CDC, apoptosis, ADCC, phagocytosis, or by a combination of two or more of these mechanisms, which express CD20 in the presence of effector cells. including cell death. Cells expressing CD20 that can be inhibited or killed using the bispecific antigen-binding molecules of the present invention include, for example, oncogenic B cells.

Antigen-binding molecules of the invention may be used, for example, in the brain and meninges, pharynx, lungs and bronchi, gastrointestinal tract, male and female reproductive tract, muscle, bone, skin and appendages, connective tissue, spleen, immune system, blood forming cells. and primary and/or metastatic tumors arising in the bone marrow, liver and urinary tract, and certain sensory organs, such as the eye. In certain embodiments, the bispecific antigen-binding molecules of the invention are used to treat one or more of the following cancers: renal cell carcinoma, pancreatic carcinoma, breast cancer, head and neck cancer, prostate cancer, malignant glioma, osteosarcoma, colorectal cancer , gastric cancer (eg, gastric cancer with MET amplification), malignant mesothelioma, multiple myeloma, ovarian cancer, small cell lung cancer, non-small cell lung cancer, synovial sarcoma, thyroid cancer, or melanoma. According to certain exemplary embodiments, the bispecific antigen-binding molecules of the invention are useful in B cell cancers (eg, Hodgkin's lymphoma, non-Hodgkin's lymphoma [NHL], precursor B cell chronic lymphocytic leukemia/small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, mantle cell lymphoma, follicular lymphoma, cutaneous follicular central lymphoma, marginal zone B-cell lymphoma, hairy cell leukemia, diffuse large B-cell lymphoma, Burkitt's lymphoma, plasmacytoma, plasma cell myeloma, post-transplant lymphoproliferative disorders, Waldenstrom's macroglobulinemia, and anaplastic large-cell lymphoma).

According to certain embodiments of the invention, the antigen-binding molecule is a B-cell lymphoma that is resistant to anti-CD20 therapy alone ( eg, resistant to rituximab therapy) or incompletely responsive ( eg, , NHL). According to another related embodiment of the present invention, a patient suffering from a B-cell lymphoma ( eg , NHL) refractory to anti-CD20 therapy ( eg , having a rituximab-refractory tumor or having relapsed or A method comprising administering an anti-CD3/anti-CD20 bispecific antigen-binding molecule disclosed herein to a patient having refractory B-cell lymphoma. Analytical/diagnostic methods known in the art, such as tumor scanning, can be used to determine if a patient has a tumor that is resistant, incompletely responsive, or refractory to anti-CD20 therapy alone.

The present invention also includes methods of treating residual cancer in a subject. As used herein, the term “residual cancer” refers to the presence or persistence of one or more cancerous cells in a subject after treatment with anti-cancer therapy.

According to certain aspects, the present invention provides a subject after administration of an anti-CD20 mono-therapy ( eg, after administration of a pharmaceutical composition comprising an anti-CD20 antibody, eg, rituximab). A method of treating a disease or disorder associated with CD20 expression ( eg , B cell lymphoma) comprising administering to a subject one or more of the bispecific antigen-binding molecules described elsewhere herein. For example, the present invention provides that the subject is administered anti-CD20 mono-therapy ( eg , rituximab treatment or equivalent treatment) on days 1, 2, 3, 4, 5, 6 After 1, 1, 2, 3, or 4 weeks, 2 months, 4 months, 6 months, 8 months, 1 year, or longer, the patient is given an anti-CD3/anti-CD20 bispecific antigen-binding molecule. A method of treating B cell lymphoma comprising administering. In another aspect, a bispecific antigen-binding molecule of the invention comprising an IgG4 Fc domain ( eg, to provide robust initial depletion of B cells) (anti-CD3/anti-CD20 bispecific antigen-binding molecule) is administered to the subject first at one or more time points, followed by administration of an equivalent bispecific antigen-binding molecule comprising a different IgG domain, eg, an IgG1 Fc domain, at subsequent time points.

Combination Therapies and Formulations

The present invention provides methods comprising administering a pharmaceutical composition comprising any of the exemplary antibodies and bispecific antigen-binding molecules described herein in combination with one or more additional therapeutic agents. Exemplary additional therapeutic agents that may be used or administered in combination with an antigen-binding molecule of the present invention include, for example , EGFR antagonists ( eg , anti-EGFR antibodies [ eg , cetux® mab or panitumumab] or small molecule inhibitors of EGFR [ eg gefitinib or erlotinib]), antagonists of other EGFR family members such as Her2/ErbB2, ErbB3 or ErbB4 ( eg anti -ErbB2, anti-ErbB3 or anti-ErbB4 antibodies or small molecule inhibitors of ErbB2, ErbB3 or ErbB4 activity), antagonists of EGFRvIII ( eg, antibodies that specifically bind to EGFRvIII), cMET antagonists ( eg , anti-ErbBIII) cMET antibody), IGF1R antagonist ( eg , anti-IGF1R antibody), B-raf inhibitor ( eg, vemurafenib, sorafenib, GDC-0879, PLX-4720), PDGFR-α inhibitor ( eg For example , anti-PCGFR-α antibodies), PDGFR-β inhibitors ( eg , anti-PDGFR-β antibodies), VEGF antagonists ( eg , VEGF-traps, eg , US 7,087,411 (herein "VEGF - also referred to as "inhibitory fusion proteins"), anti-VEGF antibodies ( eg , bevacizumab), small molecule kinase inhibitors of the VEGF receptor ( eg, sunitinib, sorafenib or pazopanib)), DLL4 antagonists ( eg, an anti-DLL4 antibody disclosed in US 2009/0142354, such as REGN421), Ang2 antagonists ( eg, an anti-Ang2 antibody disclosed in US 2011/0027286, such as , H1H685P), FOLH1 antagonist ( eg , anti-FOLH1 antibody), PRLR antagonist ( eg , anti-PRLR antibody), STEAP1 or STEAP2 antagonist ( eg , anti-STEAP1 antibody or anti-STEAP2 antibody), TMPRSS2 antagonists ( eg , anti-TMPRSS2 antibodies), MSLN antagonists ( eg , anti-MSLN antibodies), CA9 antagonists ( eg , anti-CA9 antibodies), uroplakin antagonists ( eg , anti-europlakin antibodies), monovalent CD20 antagonists ( eg , a monovalent anti-CD20 antibody, such as rituximab), and the like. Other agents that may be advantageously administered in combination with the antigen-binding molecules of the invention include cytokine inhibitors, including small-molecule cytokine inhibitors, and cytokines such as IL-1, IL-2, IL-1 -3, IL-4, IL-5, IL-6, IL-8, IL-9, IL-11, IL-12, IL-13, IL-17, IL-18 or their respective receptors. Antibodies are included. In addition, the pharmaceutical composition of the present invention ( eg, a pharmaceutical composition comprising an anti-CD3/anti-CD20 bispecific antigen-binding molecule disclosed herein) may contain "ICE": ifosfamide ( eg eg , Ifex®), carboplatin ( eg Paraplatin®), etoposide ( eg Etopophos®, Toposar®, Vepesid®, VP-16); "DHAP": examethasone ( eg Decadron®), cytarabine ( eg Cytosar-U®, cytosine arabinoside, ara-C), cisplatin ( eg Platinol®-AQ); and "ESHAP": etoposide ( eg Etopophos®, Toposar®, VePesid®, VP-16), methylprednisolone ( eg Medrol®), high dose cytarabine, cisplatin ( eg Platinol® -AQ).

In addition, the present invention relates to any of the antigen-binding molecules mentioned herein and VEGF, Ang2, DLL4, EGFR, ErbB2, ErbB3, ErbB4, EGFRvIII, cMet, IGF1R, B-raf, PDGFR-α, PDGFR- β, FOLH1, PRLR, STEAP1, STEAP2, TMPRSS2, MSLN, CA9, an inhibitor of one or more of Europlakin, or a therapeutic combination comprising any of the aforementioned cytokines, wherein the Inhibitors include aptamers, antisense molecules, ribozymes, siRNA, peptibodies, nanobodies, or antibody fragments ( eg , Fab fragments; F(ab') ₂ fragments; Fd fragments, Fv fragments; scFv; dAb fragments; or other engineered molecules such as diabodies, triabodies, tetrabodies, minibodies, and minimal recognition units). In addition, the antigen-binding molecules of the present invention may be administered in combination with, and/or co-formulated with, antiviral agents, antibiotics, analgesics, corticosteroids, and/or NSAIDs. Antigen-binding molecules of the invention may also be administered as part of a treatment regimen that also includes radiation therapy and/or conventional chemotherapy.

The additional therapeutically active ingredient(s) may be administered immediately prior to, concurrently with, or immediately after administration of the antigen-binding molecule of the present invention (for purposes of this disclosure, such administration regimens are It is contemplated that the antigen-binding molecule is administered "in combination with" an additional therapeutically active ingredient).

The present invention includes pharmaceutical compositions in which an antigen-binding molecule of the present invention is co-formulated with one or more of the additional therapeutically active ingredient(s) described elsewhere herein.

dosing regimen

According to certain embodiments of the invention, multiple doses of an antigen-binding molecule ( eg, an anti-CD3 antibody or a bispecific antigen-binding molecule that specifically binds to CD20 and CD3) are administered over a defined time course. can be administered to a subject. A method according to this aspect of the invention comprises sequentially administering to a subject multiple doses of an antigen-binding molecule of the invention. As used herein, "sequentially administering" means administering each dose of an antigen-binding molecule at different times, eg, on different days separated by predetermined intervals (eg hours, days, weeks or months). means to be administered to a subject. The present invention provides a patient with a single starting dose of an antigen-binding molecule, followed by one or more secondary doses of an antigen-binding molecule, followed by, optionally, one or more tertiary doses of an antigen-binding molecule. It includes a method comprising sequentially administering.

The terms "starting dose", "second dose" and "tertiary dose" refer to a temporal sequence of administration of an antigen-binding molecule of the invention. Thus, a "starting dose" is the dose administered at the beginning of a treatment regimen (also referred to as a "baseline dose"); A “second dose” is a dose administered after the initial dose; A “tertiary dose” is a dose administered after a second dose. The initial, secondary, and tertiary doses may all contain the same amount of antigen-binding molecule, but will generally differ from each other in terms of frequency of administration. However, in certain embodiments, the amount of antigen-binding molecule contained in the initial, secondary and/or tertiary doses will differ from each other (eg adjusted up or down as appropriate) over the course of treatment. In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered as “loading doses” at the beginning of the treatment regimen, followed by less frequent administration. Subsequent doses (eg, “maintenance doses”) are administered.

In one exemplary embodiment of the invention, each second and/or third dose is 1 to 26 (e.g., 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½, 15, 15½, 16, 16½, 17, 17½, 18, 18½, 19, 19½, 20, 20½, 21, 21½, 22, 22½, 23, 23½, 24, 24½, 25, 25½, 26, 26½, or longer) weeks. As used herein, the phrase "immediately preceding dose" refers to the dose of an antigen-binding molecule that is administered to a patient prior to administration of the immediately next dose in the sequence, without an intervening dose, in a sequence of multiple administrations.

Methods according to this aspect of the invention include a second and/or tertiary dose of an antigen-binding molecule ( eg, an anti-CD3 antibody, or a bispecific antigen-binding molecule that specifically binds to CD20 and CD3) may include administering to the patient any number of For example, in certain embodiments, only a single secondary dose is administered to the patient. In another embodiment, two or more ( eg , 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Similarly, in certain embodiments, only a single tertiary dose is administered to the patient. In another embodiment, two or more ( eg , 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.

In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each second dose may be administered to the patient 1 to 2 weeks after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each third dose may be administered to the patient 2 to 4 weeks after the immediately preceding dose. Alternatively, the frequency with which the second and/or third doses are administered to the patient may vary over the course of the treatment regimen. The frequency of administration can also be adjusted during the course of treatment by the physician according to the needs of the individual patient according to the clinical trial.

Diagnostic Uses of Antibodies

Anti-CD3 antibodies of the present invention may also be used to detect and/or measure CD3, or CD3-expressing cells, in a sample, eg , for diagnostic purposes. For example, an anti-CD3 antibody, or fragment thereof, can be used to diagnose a condition or disease characterized by abnormal expression ( eg , over-expression, under-expression, lack of expression, etc.) of CD3. An exemplary diagnostic assay for CD3 can include, for example , contacting a sample obtained from a patient with an anti-CD3 antibody of the invention, wherein the anti-CD3 antibody is labeled with a detectable label or reporter molecule. has been Alternatively, an unlabeled anti-CD3 antibody may be used in diagnostic applications in combination with a second antibody that is itself detectably labeled. A detectable label or reporter molecule may be a radioactive isotope such as ³ H, ¹⁴ C, ³² P, ³⁵ S, or ¹²⁵ I; fluorescent or chemiluminescent moieties such as fluorescein isothiayanate, or rhodamine; or enzymes such as alkaline phosphatase, beta-galactosidase, horseradish peroxidase, or luciferase. Specific exemplary assays that can be used to detect or measure CD3 in a sample include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and fluorescence-activated cell sorting (FACS).

A sample that can be used in a CD3 diagnostic assay according to the present invention includes any tissue or fluid sample that can be obtained under normal or pathological conditions from a patient that contains detectable amounts of the CD3 protein or fragment thereof. Generally, the level of CD3 in a particular sample obtained from a healthy patient ( eg, a patient not suffering from a disease or condition associated with abnormal CD3 levels or activity) will be measured to initially establish a baseline, or standard, level of CD3. . This baseline level of CD3 can then be compared to the level of CD3 measured in a sample obtained from an individual suspected of having a CD3 related disease or condition.

Example

The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and explanation of how to make and use the methods and compositions of the present invention, which are within the scope of what the inventors regard as the present invention. is not intended to limit Efforts have been made to ensure accuracy with respect to numbers used (eg amounts, temperature, etc.), but some experimental errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

Example 1. Generation of anti-CD3 antibodies

Anti-CD3 antibodies are obtained by immunizing a ^VELOIMMUNE® mouse ( ie , an engineered mouse comprising DNA encoding human immunoglobulin heavy chain and kappa light chain variable regions) with cells expressing CD or with DNA encoding CD3. It became. Antibody immune responses were monitored by CD3-specific immunoassay. When the desired immune response was achieved, splenocytes were harvested and fused with mouse myeloma cells to preserve their viability and form a hybridoma cell line. Hybridoma cell lines were screened and selected to identify cell lines that produce CD3-specific antibodies. Using this technique, several anti-CD3 chimeric antibodies ( ie , antibodies with human variable domains and mouse constant domains) were obtained. In addition, several fully human anti-CD3 antibodies were isolated directly from antigen-positive B cells without fusion to myeloma cells, as described in US 2007/0280945A1.

Certain biological properties of exemplary anti-CD3 antibodies generated according to the methods of these Examples are detailed in the Examples set forth below.

Example 2. Heavy Chain Light Chain Variable Region Amino Acid and Nucleic Acid Sequences

Table 1 presents the amino acid sequence identifiers of the heavy and light chain variable regions and CDRs of selected anti-CD3 antibodies of the present invention. Corresponding nucleic acid sequence identifiers are presented in Table 2.

Antibodies are typically denoted herein according to the following nomenclature: an Fc prefix ( eg , “H1H”, “H1M”, “H2M”, etc.) followed by a numerical identifier ( eg, “2712 as shown in Table 1). ", "2692", etc.) followed by a "P", "N" or "B" suffix. Thus, according to this nomenclature, antibodies may be referred to herein as, for example , "H1H2712N", "H1M2692N", "H2M2689N", and the like. The H1H, H1M, and H2M prefixes to antibody names used herein indicate the specific Fc region isotype of the antibody. For example, the "H1H" antibody has a human IgG1 Fc, the "H1M" antibody has a mouse IgG1 Fc, and the "H2M" antibody has a mouse IgG2 Fc (all variable regions denoted by the initial 'H' in the antibody name). As a bar, it is completely human). As will be understood by those skilled in the art, antibodies with a particular Fc isotype can be converted to antibodies with a different Fc isotype ( e.g., an antibody with a mouse IgG1 Fc, an antibody with a human IgG4, etc. can be converted to), in any case, the variable domains (including CDRs) represented by the numerical identifiers shown in Table 1 will remain the same, and the binding properties are the same or substantially the same regardless of the nature of the Fc domain. is predicted to be similar to

Control constructs used in the examples below

Various control constructs (anti-CD3 antibodies) were included in the following experiments for comparison purposes: " OKT-3 ", human T-cells available from American Type Culture Collection (ATCC) under catalog number CRL-8001. mouse monoclonal antibodies against surface antigens; and " SP34 ", a commercially available mouse monoclonal antibody obtained from Biolegend, San Diego, CA (Cat. No. 302914), reactive against the epsilon chain of the T3 complex on human T lymphoid cells;

Example 3. Surface Plasmon Resonance Induced Binding Affinity and Kinetic Constants of Human Monoclonal Anti-CD3 Antibodies

Binding affinities and kinetic constants of human monoclonal anti-CD3 antibodies were measured using antibody-capture format (Table 3, Table 5 and Table 7) or antigen-capture format (Table 4, Table 6 and Table 8). Measured by surface plasmon resonance at 25°C. Measurements were performed on a T200 Biacore instrument.

In the antibody-capture format, the Biacore sensor surface is either a rabbit anti-mouse Fc for hybridoma capture (antibody prefix H1M or H2M) or a mouse anti-human Fc surface for human IgG formatted antibody (antibody prefix H1H). derivatized. Soluble heterodimeric CD3 protein (hCD3-epsilon/hCD3-delta; SEQ ID NO: 1370/ 1371) was injected onto the antibody captured surface and the binding reaction was recorded. See Davis et al. (US2010/0331527), heterodimeric CD3 protein was purified.

In the antigen-capture format, heterodimeric CD3 protein was captured using rabbit anti-mouse Fc or mouse anti-human Fc, and the reactive antibody was injected over the captured antigen.

Antibodies were analyzed in a conventional bivalent format (Tables 3 to 6) or in a monovalent one-arm configuration in which the second Fab from the antibody was removed and only the Fc portion (CH2-CH3) was expressed (Tables 7 and 8). did

Kinetic association (k _a ) and dissociation (k _d ) rate constants were determined by processing and fitting the data to a 1:1 binding model using Scrubber 2.0 curve fitting software. Association dissociation equilibrium constants (K _D ) and dissociation half-lives (t _1/2 ) were calculated from kinetic rate constants as follows: K _D (M) = k _d / k _a ; and t _1/2 (min) = (ln2/(60*k _d ). NT = not tested; NB = no binding observed.

As shown in Tables 3-8, several anti-CD3 antibodies of the present invention bind CD3 with high affinity in an antibody-capture or antigen-capture format.

Example 4. Anti-CD3 antibodies bind and proliferate human T-cells

Anti-CD3 antibodies of the invention were tested for their ability to bind to and induce proliferation of human T-cells. Binding was assessed using Jurkat cells (CD3+ human T-cell line), while proliferation of peripheral blood mononuclear cells (PBMCs) was assessed using ATP-catalyzed quantification (CellTiter Glo®). The anti-CD3 antibody OKT3 served as a positive control and an irrelevant isotype matched antibody served as a negative control.

FACS data were acquired using the following protocol: 2×10 ⁵ cells per well were incubated with serially diluted antibodies for 30 min on ice. After incubation, cells were washed, secondary antibodies were added, and incubated for an additional 30 minutes. After incubation, cells were washed, resuspended in cold PBS containing 1% BSA and analyzed by flow cytometry using viable Jurkat cells gated by side and forward scatter. EC ₅₀ for cell binding titrations using Prism software were determined as values calculated using 4-parameter non-linear regression analysis.

Proliferation data were obtained using the following protocol: Human PBMCs (5x10 ⁴ /well) were cultured in 96-well plates at 37° C. for 72 h with anti-CD3 and a fixed concentration of commercial anti-CD28 antibody (200 ng/ml). Incubated with a 3-fold serial dilution. After incubation, CellTiter Glo® was added and luminescence was measured using a VICTOR X5 multi-label plate reader (PerkinElmer). EC ₅₀ (ATP promoted quantification) of cell viability was calculated using a 4-parameter non-linear regression analysis in GraphPad Prism.

The results of binding and proliferation experiments are summarized in Tables 9-11.

As shown in Tables 7-9, most of the anti-CD3 antibodies of the present invention bound to human T-cells and induced T-cell proliferation.

Example 5. Anti-CD3 antibodies bind to and proliferate monkey T-cells

A subset of the anti-CD3 antibodies of the invention were tested for their ability to bind to and induce proliferation of monkey T-cells.

FACS data were acquired using the following protocol: 2×10 ⁵ cells per well were incubated with serially diluted antibodies for 30 min on ice. After incubation, cells were washed, secondary antibodies were added, and incubated for an additional 30 minutes. After incubation, cells were washed, resuspended in cold PBS containing 1% BSA and analyzed by flow cytometry. CD4+ monkey T cells were gated by side and forward scatter and for the CD2+CD4+CD20− population. EC ₅₀ for cell binding titrations were calculated using 4-parameter non-linear regression analysis in GraphPad Prism.

Proliferation data were obtained using the following protocol: Freshly isolated cynomolgus monkey derived PBMCs (5x10 ⁴ /well) were commercially available at a fixed concentration and anti-CD3 antibody in 96 well plates for 72 h at 37°C. Incubated with 3-fold serial dilutions of anti-CD28 antibody (500 ng/ml). After incubation, CellTiter Glo® was added and luminescence was measured using a VICTOR X5 multi-label plate reader (PerkinElmer). EC ₅₀ (ATP promoted quantification) of cell viability was calculated using a 4-parameter non-linear regression analysis in GraphPad Prism.

The results of binding and proliferation experiments are summarized in Tables 12 and 13.

As shown in Tables 12 and 13, several anti-CD3 antibodies of the present invention bound CD2+CD4+ monkey T-cells and induced their proliferation. OKT3 did not induce monkey PBMC proliferation, while SP34 was active against monkey PBMC.

Example 6. Anti-CD3 mAbs support T-cell-mediated killing of tumor cells

The ability of anti-CD3 antibodies to redirect T-cell mediated killing through Fc/FcR interactions was studied using a calcein-based U937 killing assay. Briefly, human PBMCs were isolated over Ficoll-Paque and activated over the course of several days with media containing human IL-2 (30 U/ml) and T-cell activation beads (anti-CD3/CD28). u937 cells were labeled with calcein and then incubated with activated T-cells at a 10:1 effector:target ratio using a 3-fold serial dilution of the antibody over the course of 3 hours at 37°C. After incubation, the plate was centrifuged and the supernatant was transferred to a translucent black clear bottom plate for fluorescence analysis. EC ₅₀ values, defined as the molar concentration of CD3 antibody that induces 50% cytotoxicity, were calculated using 4-parameter non-linear regression analysis in GraphPad Prism. Results using hybridoma antibodies, human Fc antibodies, and monovalent one-arm antibodies are shown in Table 14, Table 15, and Table 16, respectively.

As shown in Tables 14-16, most anti-CD3 antibodies, and OKT3, supported redirected T-cell mediated killing in this assay system. The observed killing, thought to be dependent on the Fc of an antibody linked to the Fc receptor on U937 cells, leading to clustering of CD3 on adjacent T-cells, was inhibited by the addition of non-specific human IgG (data not shown). not).

Example 7. Generation of bispecific antibodies that bind to CD3 and CD20

Bispecific antibodies comprising an anti-CD3-specific binding domain and an anti-CD20-specific binding domain were constructed using standard methods, wherein the heavy and light chains from the anti-CD3 antibody are derived from the anti-CD20 antibody. bound to the heavy chain of The anti-CD3 antibodies used to construct the bispecific antibodies of this Example were obtained by immunizing VeloImmune® mice with cells expressing CD3 or with DNA encoding CD3, or in the case of BS3/20-007 and -009. It was obtained from a known anti-CD3 antibody ( ie the anti-CD3 antibody "L2K" set forth in WO2004/106380). The anti-CD20 antibody used to construct the bispecific antibodies of this example is as set forth in US 7,879,984.

Bispecific antibodies generated according to this Example comprise two separate antigen-binding domains ( ie , binding arms). The first antigen-binding domain comprises a heavy chain variable region derived from an anti-CD20 antibody (“CD20-VH”) paired with a light chain variable region derived from an anti-CD3 antibody (“CD3-VL”).

Pairing CD20-VH/CD3-VL creates an antigen-binding domain that specifically recognizes CD20. The second antigen-binding domain comprises a heavy chain variable region derived from an anti-CD3 antibody (“CD3-VH”) paired with a light chain variable region derived from an anti-CD3 antibody (“CD3-VL”). Pairing CD3-VH/CD3-VL creates an antigen-binding domain that specifically recognizes CD3. The same CD20-VH was used in all bispecific antibodies generated in this example and is termed “CD20-VH-A” (except for BS3/20-009, a different antibody termed “CD20-VH-B”). CD20-VH was used). However, several different CD3-VH and CD3-VL components (named "CD3-VH-A, CD3-VH-B, etc., and CD3-VL-A, CD3-VL-B, etc., different anti-CD3 antibodies) were used for different bispecific antibodies in the examples below.

A summary of the constituent parts of the antigen-binding domains of the various bispecific antibodies prepared according to this Example is presented in Table 17.

Tables 18 and 19 present the amino acid sequence identifiers for the various heavy chain variable regions (Table 18) and light chain variable regions (Table 19) of the bispecific antibodies of this Example, and their corresponding CDRs.

Tables 20 and 21 also show sequence identifiers for nucleotide sequences encoding various heavy chain variable regions (Table 20) and light chain variable regions (Table 21), and their corresponding CDRs, of the bispecific antibodies of this Example. present them

In addition to the bispecific antibodies described above, the following control antibodies were also used in certain experiments presented in the Examples that follow:

Control I : "OKT-3", a monoclonal antibody directed against human T-cell surface antigen as set forth in US 4,361,549 and available from hybridoma CRL-8001 (American Type Culture Collection, Manassas, Va.).

Control II : antibody "SP34" reactive against the epsilon chain of the T3 complex on human T lymphoid cells, available from BD Pharmagen, Cat # 55052.

Control III : anti-CD20 therapeutic antibody having the heavy and light chain sequences of Rituxan (Rituximab) as disclosed in US 5,736,137.

Control IV : HCVR/LCVR amino acid sequence pair disclosed in US 7,879,984 and herein SEQ ID NOs: 1242/1346 and HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acids SEQ ID NOs: 1244-1246-1248-1348-1350-1352 A monoclonal anti-CD20 antibody designated "3B9-10" presented as an antibody comprising the sequence.

Control V : an HCVR/LCVR amino acid sequence pair disclosed in US 7,879,984, SEQ ID NOs: 1354/1362, and HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acids SEQ ID NOs: 1356-1358-1360-1364-1366-1368 A monoclonal anti-CD20 antibody designated “10F2-13” presented as an antibody comprising the sequence.

Example 8. CD20 x CD3 bispecific antibody binds selectively to Jurkat, Raji and monkey T-cells

The CD20 x CD3 bispecific antibody and control constructs presented in Example 1 were administered via FACS to Jurkat (CD3+, CD20 - human T-cell line), Raji (CD3-, CD20+ human B-cell line), or cynomolgus PBMC. (“mkT cells”).

FACS data were acquired using the following protocol: 2×10 ⁵ cells per well were incubated with serially diluted antibodies for 30 min on ice. After incubation, cells were washed, the appropriate secondary antibody (Jurkat, RAJI cells) or a cocktail of secondary antibodies (for cyno PBMCs) was added and incubated for an additional 30 minutes. After incubation, cells were washed, resuspended in cold PBS containing 1% BSA and analyzed by flow cytometry on a BD FACS Canto II. Jurkat and Raji cells were gated by side and forward scatter, while cynomolgus T cells were also gated for the CD2+CD4+ population. The EC ₅₀ for cell binding titration was determined as a value calculated using a 4-parameter non-linear regression analysis using Prism software. The results are shown in Table 22.

As shown in Table 22, the panel of antibodies tested showed a range of binding affinities to various cell lines depending on their specificity. Bispecific antibodies (BS3/20-001, -002, -003, -004 and -005) showed the ability to bind both human target strains. A subset of antibodies also showed the ability to bind to cynomolgus cells (Control II, BS3/20-001 and BS3/20-003). Anti-CD3 control I (OKT3), anti-CD3 control II (SP34), and anti-CD20 control IV bound to Jurkat, cynomolgus T cells, and RAJI, respectively.

Example 9. CD20 x CD3 bispecific antibodies induce PBMC proliferation in vitro

The ability of selected CD20 x CD3 bispecific antibodies and control constructs to stimulate peripheral blood mononuclear cells (PBMC) and induce proliferation was assessed using ATP-catalyzed quantification (CellTiter Glo®). Activation of PBMCs results in the release of cytokines, which induce cell proliferation.

Proliferation data were obtained using the following protocol: human or cynomolgus monkey derived PBMCs (5x10 ⁵ /well) were subjected to 3-fold serial incubation of anti-CD3xCD20 or control antibodies in 96-well plates for 72 h at 37°C. It was incubated with the diluent. After incubation, CellTiter Glo® was added and luminescence was measured using a VICTOR X5 multi-label plate reader (PerkinElmer). EC ₅₀ (ATP promoted quantification) of cell viability was measured using Prism software. These values were calculated using a 4-parameter non-linear regression analysis and are shown in Table 23.

As shown in Table 23, all CD20 x CD3 bispecific antibodies of the present invention were activators of human or cynomolgus PBMC. In general, anti-CD3 monospecific bivalent parental antibodies (Control I and Control II) were 2-10 fold more potent than their bispecific counterparts. Control I (OKT3) did not induce monkey PBMC proliferation, while control II (SP34) was active against both human and monkey PBMC.

Example 10. CD20 x CD3 bispecific antibody activates T-cells in human whole blood and induces IFN-gamma release and CD25 upregulation

Selected CD20 x CD3 bispecific antibodies were tested for their ability to activate T-cells in human whole blood. The extent of T-cell activation was determined by measuring interferon-gamma (IFN-γ) secretion and upregulation of CD8+ T cells.

Interferon-gamma (IFN-γ) secretion was quantified by combining heparinized whole blood with 5-fold serial dilutions of the bispecific antibody in 96-well plates. After 20 hours, plates were centrifuged for 5 minutes and plasma was removed for ELISA analysis to measure IFNγ levels. Inferred IFNγ concentrations were plotted against antibody concentrations and EC ₅₀ values were calculated using 4-parameter non-linear regression analysis using Prism software.

For analysis of CD25 expression on CD8+ T-cells, after incubation with antibody and removal of plasma, 150 μl of blood was transferred to a deep well plate and lysed with 1.5 mL RBC Lysis Buffer for 15 minutes. Cells were washed twice, blocked with hFcR blocking reagent for 10 minutes at room temperature, then incubated with antibodies directly conjugated to CD2, CD19, CD4, CD8, and CD25 for 30 minutes at 4°C. Cells were then washed twice before analysis using a FACSCanto cytometer and FlowJo software.

The percentage of CD2+CD8+ cells expressing the activation marker CD25 was plotted against antibody concentration and EC ₅₀ values were calculated using 4-parameter non-linear regression analysis using Prism software. The results are shown in Table 24.

As shown in Table 24, the CD20 x CD3 bispecific antibody had a slightly higher EC ₅₀ value for IFNγ ranging from 390 pM to 2 nM and an EC ₅₀ value ranging from 130 to 290 pM, and the CD25 on CD8+ T cells in whole blood. mediated upregulation. BS3/20-004 was slightly less potent than BS3/20-001 and BS3/20-003 in mediating CD25 upregulation and IFNγ production, as measured by EC ₅₀ , but BS3/20-004 was significantly less potent in whole blood cultures. was able to induce greater IFNγ levels.

Example 11. CD20 x CD3 bispecific antibodies induce T-cell mediated cytotoxicity against rituximab resistant cell lines

The ability of selected CD20 x CD3 bispecific antibodies and control constructs to mediate complement-dependent cytotoxicity (CDC) and T-cell mediated cytotoxicity was evaluated using parental Raji cells and the Raji SCID line. The latter (Raji SCID strain) was derived from individual anti-CD20 resistant tumors isolated from immunodeficient mice injected subcutaneously with Raji cells after treatment with the anti-CD20 mAb rituximab. In this example, 4 cell lines (Raji SCID 1 to 4) were used.

Expression of CD20 and the complement inhibitory molecules CD55 and CD59 on the Raji cell line was measured by FACS. Briefly, 1x10 ⁶ cells were incubated for 30 minutes in separate tubes with antibodies directly conjugated to CD20, CD55 and CD59. Cells were washed twice before FACS acquisition by FACSCanto cytometer and analysis with FlowJo software.

To determine the ability of anti-CD20 and anti-CD3xCd20 antibodies to mediate T-cell directed killing of Raji cell lines, calcein-labeled Raji cells were pre-activated T cells (rhIL-2 (30 U/mL) and ficoll-isolated human PBMC activated with anti-CD3/CD28 activation beads) and incubated at 37° C. for 2 hours with a 3-fold serial dilution starting at 2 nM. After incubation, the plate was centrifuged and the supernatant was transferred to a translucent black clear bottom plate for fluorescence detection at 530 nm at 485 nm emission. Percent cytotoxicity was determined for spontaneous (target cells alone) and maximal release (target cells lysed with detergent) values. EC ₅₀ values were calculated using 4-parameter non-linear regression analysis using Prism software.

To measure the activity of the antibody in mediating CDC, the Raji cell line was incubated with 5% normal human serum complement and a 3-fold serial dilution of the antibody starting at 100 nM. After incubation at 37° C. for 4.5 hours, cell death was measured using CellTiter Glo®. Percent cytotoxicity was determined for spontaneous (target cells alone) and maximal release (target cells lysed with detergent) values. EC ₅₀ values were calculated using 4-parameter non-linear regression analysis using Prism software.

The results are shown in Table 25.

Compared to the parental Raji cells, two of the four Raji SCID cell lines (Table 25; Raji SCID cell lines 1 and 3) showed reduced expression of CD20 and a significant number of cells expressing the complement inhibitory molecules CD55 and CD59. expressed as a higher percentage. Sensitivity of Raji SCID cells to CDC mediated by anti-CD20 or anti-CD20 x CD3 antibodies depended on the percentage of CD55/CD59 expressing cells, but not on the level of CD20, increasing CD55/CD59 on target cells expression inhibited CDC.

Anti-CD20 antibodies (Control IV & Control III [Rituximab]) were more potent than anti-CD20 x CD3 (BS3/20-007) in mediating CDC as the bispecific is monovalent for CD20. However, in contrast to CDC, T-cell mediated cytotoxicity does not affect CD20 or CD55/CD59, as all cell lines were equally susceptible to apoptosis by activated T-cells in the presence of anti-CD20 x CD3 bispecific antibodies. was not dependent on Additionally, the bispecific antibody was 100-1000 fold more potent in mediating T-cell dependent killing of Raji cells than the anti-CD20 antibody in a CDC assay.

Example 12. CD25 Upregulation on CD8+ T-cells Depends on CD20 Concentration in the Presence of CD20 x CD3 Bispecific Antibody

To evaluate whether higher concentrations of target cells (CD20+ lymphomas) could result in increased potency of the CD20 x CD3 bispecific antibody, human peripheral blood mononuclear cells (PBMCs) were assayed in a Burkitt's lymphoma-derived cell line, i.e. , Raji's co-cultured in the presence of

CD25 upregulation on CD8+ cells was measured using the following protocol: human PBMC (5x10 ⁵ /mL) isolated via centrifugation of mononuclear-cell enriched leukapharesis-induced blood over Ficoll. , incubated at 37° C. in 96-well flat-bottom plates with 5-fold serial dilutions of the bispecific antibody in the presence (1× ^{10 5} /mL) or absence of Raji cells. After 48 hours, cells were washed 2x, blocked with hFcR blocking reagent for 10 minutes at room temperature, followed by incubation with antibodies directly conjugated to CD2, CD19, CD4, CD8, and CD25 at 4°C for 30 minutes. cultured. After staining, cells were washed twice before FACS acquisition by FACSCanto cytometer and analysis using FlowJo software. The percentage of activated CD2+CD8+ T cells expressing CD25 was plotted against antibody concentration and EC ₅₀ values were calculated using 4-parameter non-linear regression analysis using Prism software. The results are shown in Table 26.

As shown in Table 26, activated T-cells when cultured in the presence of Raji (target) cells showed upregulation of CD25, and a subsequent 100-fold decrease in their EC ₅₀ values.

Example 13. CD20 x CD3 bispecific antibody induces cytotoxicity against Raji cells in the presence of activated T-cells

The ability of CD20 x CD3 bispecific antibodies to redirect T-cell mediated killing on CD20-expressing Raji cells was tested in an in vitro cytotoxicity assay. In addition, the ability of both the bispecific and parental anti-CD3 antibodies to kill U937 cells through Fc/FcR interactions was also studied.

The calcein killing assay was performed using the following protocol: Human and cynomolgus PBMC were isolated over ficoll-Plaque or over Lympholyte mammalian cell dissociation medium, respectively. Medium containing recombinant human IL-2 (30 U/ml) and T-cell activating beads (anti-CD3/CD28 for human PBMCs, anti-CD2/CD3/CD28 for cynomolgus PBMCs) was used for several days. Isolated PBMCs were activated over the course.

Target cells (Raji for CD20 mediated killing and U937 for FcR mediated killing) were labeled with calcein and a 3-fold serial dilution of antibody over the course of 3 hours at 37°C along with activated T-cells. Water was used to incubate at a 10:1 effector:target ratio. After incubation, the plate was centrifuged and the supernatant transferred to a translucent black clear bottom plate for fluorescence analysis. The EC ₅₀ , defined as the molar concentration of the bispecific antibody that induces 50% cytotoxicity, was determined using Prism. The values were calculated using 4-parameter non-linear regression analysis. The results are summarized in Table 27.

As shown in Table 27, bispecific CD20 x CD3 antibodies containing human-specific or human/cynomolgus cross-reactive anti-CD3 arms are specific for cytotoxicity to Raji cells in the presence of human activated T cells. could be redirected to In the presence of cynomolgus activated T cells, Raji are killed when they are incubated with BS3/20-001 or BS3/20-003, a bispecific antibody with an anti-CD3 arm that activates monkey T-cells It became. All bispecific antibodies and control I, anti-CD3 mAbs showed activity in the U937 Fc/FcR dependent killing assay. This activity could be blocked by the addition of a blocking non-specific human IgG to the reaction (data not shown).

Example 14. CD3 x CD20 bispecific antibody can deplete CD19+ B-cells in mice reconstituted with human immune cells

To determine the in vivo potency of CD3 x CD20 bispecific antibody administration, changes in CD19+ B-cell and CD2+ T-cell levels were measured after 10 μg to 0.1 μg of anti-CD3xCD20 bispecific antibody to mice reconstituted with human immune cells. After administration of μg was examined via FACS.

Briefly, neonatal BALB/Rag2 ^null /γ _c ^null mice were irradiated with 2 x 150 Rads and reconstituted with 4 x 10 ⁵ human CD34 ⁺ hematopoietic stem precursor cells via intrahepatic injection. After 12 weeks, the composition of the reconstituted human immune system in peripheral blood was measured by flow cytometry. Typically, by 3 months after reconstitution, 10% to 60% of the peripheral white blood cells are human CD45+, of which 40% to 70% are B cells, 15% to 40% are T-cells, and the remainder are subpopulations. of natural apoptosis and dendritic cells.

Five months after reconstitution, mice received either 10 μg or 0.1 μg of anti-CD3×CD20 bispecific antibody BS3/20-007, 10 μg of a monovalent one-armed CD3 antibody (BS3/20-009, see Table 1) or 10 μg of An irrelevant hIgG isotype control was injected intraperitoneally. 1, 8, and 25 days after injection, mice were retro-orbitally bled, and immune cell populations in peripheral blood were measured by flow cytometry (FACS).

For FACS analysis, 100 μl of blood was incubated with 1.5 ml RBC lysis buffer in an Eppendorf tube for 3 minutes. Cells were centrifuged at 0.4xg for 5 min, washed 2x with FACS wash (PBS + 3% FBS), and blocked using mouse Fc blocking reagent for 10 min at room temperature. Cells were then incubated with antibodies directly conjugated to CD2, CD3, CD19, CD4, CD8, hCD45, hHLA-DR, and mCD45 for 30 minutes at 4°C. After staining, cells were washed twice before FACS acquisition by FACSCanto cytometer and analysis using FlowJo software. The results are shown in Table 28.

As shown in Table 28, a single 10 μg dose of the anti-CD3×CD20 bispecific antibody BS3/20-007 resulted in the disappearance of circulating hCD45+ cells in 2 of 2 treated mice that did not recover over the length of the experiment. caused A single 0.1 μg dose of BS3/20-007 reduced circulating hCD45+ cells, including CD19+ B-cells and CD2+ T-cells, 24 hours after injection in 2 of 3 treated mice. Once depleted, the percentage of hCD45+ cells did not recover significantly in responding mice treated with 0.1 μg BS3/20-007. However, what cells retained in these mice were predominantly hCD2+ T-cells, and CD19+ B cells were not present in responding mice after 25 days of treatment. A single 10 μg dose of a monovalent 1-arm CD3 antibody (BS3/20-009) also resulted in a sustained but normal reduction of CD45+ cells, specifically CD2+ T-cells, in 2 of 2 treated mice. caused A single 10 μg single dose of an irrelevant hIgG1 control had no significant effect on the percentage of circulating hCD45+, hCD19+, or hCD2+ cells.

Example 15. Treatment with a CD20 x CD3 bispecific antibody reduces Raji tumor volume in NOD/SCID mice

To evaluate the efficacy of selected anti-CDxCD20 bispecific antibodies in reducing Raji tumor growth, NOD/SCID mice (Taconic) were implanted subcutaneously with a mixture of 2x10 ⁶ Raji tumor cells and 8x10 ⁶ human PBMCs. Mice were treated three times per week with human Fc (hFc) or CD3xCD20 bispecific antibody (BS3/20-007) at a dose of 1 μg per mouse starting on the day of tumor implantation (N=20 mice per treatment group). Reagents were delivered by intraperitoneal (ip) injection. Tumor size was measured three times per week using a caliper, and tumor volume was calculated as volume = (length x width ² )/2. The results are shown in FIG. 1 .

In a second experiment, NOD/SCID mice were implanted subcutaneously with a mixture of 2x10 ⁶ Raji tumor cells and 4x10 ⁶ human PBMCs. Treatment with the CD3xCD20 bispecific antibody (BS3/20-007) or control reagent (hFc) was initiated 7 days after tumor implantation to allow tumors to be detectable. Mice were treated twice per week at a dose of 1 μg per mouse (N=6 mice per treatment group). Reagents were injected subcutaneously away from the site of tumor implantation. Tumor size was measured twice per week using calipers, and tumor volume was calculated as volume = (length x width ² )/2. The results are shown in FIG. 2 .

This Example demonstrates that treatment with the CD3xCD20 bispecific antibody BS3/20-007 was effective in inhibiting tumor growth both at the time of tumor implantation and at the time of tumor establishment. Tumor volume in mice was reduced 25 days after implantation in both studies compared to controls.

Example 16. CD20 x CD3 bispecific antibody depletes the B-cell population of cynomolgus monkeys and has a pharmacokinetic profile typical of monoclonal antibodies

Preliminary non-GLP toxicology and pharmacology studies were conducted in cynomolgus monkeys ( Macaca fascicularis ) to determine the ability of the CD3xCD20 bispecific antibody to deplete the B-cell population in these animals. Male animals were organized into 3 cohorts. Cohort 1 received bispecific antibody BS3/20-001 and included 3 different dosing groups (0.01, 0.10 and 1.00 mg/kg) with 3-4 animals per dosing group. Cohort 2 was a two-animal cohort that received a low dose of anti-CD20 control antibody (Control V; 0.01 mg/kg). Cohort 3 was a 4-animal cohort that received a high dose of anti-CD20 control antibody (Control III; 1.0 mg/kg). Bleeds were drawn on day -7 and at the beginning of dosing to establish baseline levels for B and T cells in these animals. Drug doses of 0.01, 0.10, or 1.00 mg/kg were administered by iv infusion, and blood was drawn 5 minutes, 5 hours, and 1, 4, 7, and 14 days after dosing. After 14 days post-dose, blood was drawn every 2 weeks until the end of the study. Blood samples were analyzed for B and T cell markers by FACS and the absolute number of these cell types was determined. Serum samples were also analyzed for cytokine levels (IFNγ, IL-2, IL-6 and TNFα) using standard assay methods. RM results are shown in FIG. 3 (B-cells), FIG. 4 (T-cells), and FIGS. 5A-5D (cytokines).

As shown in this Example, administration of the CD3xCD20 bispecific antibody resulted in depletion of circulating B-cells to baseline levels by the first time point measured (Day 1). This depletion was not seen in the control animal cohort. B-cell depletion in the bispecific cohort was maintained up to 2 weeks post-dose, followed by a gradual recovery of B-cell levels in the 0.01 and 0.10 mg/kg dose cohorts until the experiment concluded at approximately 11 weeks post-dose. . However, the 1.0 mg/kg cohort did not show recovery of B-cell levels during the experimental period (11 weeks). In addition, T-cell levels were monitored in this experiment. A transient loss of circulating T-cells was observed 1 day after dosing in the bispecific cohort. T-cell levels returned to baseline levels in these cohorts by the 4-day time point and remained at these baseline levels until the end of the experiment. In addition, serum cytokine levels for BS3/20-001 at 5 hours showed dose- and time-dependent responses consistent with T-cell activation (see FIGS. 5A to 5D ).

In addition, gene expression levels in peripheral blood were analyzed during this experiment. Blood samples were obtained from the animals at two pre-dose time points (7 days pre-dose and immediately prior to dosing) and at 5, 24, 72, 96, and 168 hours post-dose. RNA was isolated from these samples and analyzed by microarray. A significant decrease was observed in gene expression of B-cell markers in animals treated with the bispecific antibody when compared to pre-dose levels and gene expression levels from the control group; This effect was similar to that observed in samples obtained from animals treated with 1.0 mg/kg control III (anti-CD20 antibody corresponding to rituximab). The observed change in B-cell marker expression corresponds to the loss of B-cells detected in the blood of the treated animals. Expression of T-cell marker genes in samples from animals treated with the CD3xCD20 bispecific antibody showed an initial decrease followed by a return to normal levels by the 24 hour time point. In addition, genes associated with the inflammatory response showed initial upregulation in animals in the bispecific cohort, but recovered to normal or subnormal levels after 24 hours. Finally, examination of the raw intensity of the CD20 gene expression signal revealed greater depletion of B-cells from treatment of animals with the CD3xCD20 bispecific antibody than from treatment of animals with the control anti-CD20 antibody. suggests (See Figure 6 and Table 29).

As shown in Table 29, the raw intensity of the CD20 signal at 7 days post-dose remained at background levels in all but one of the CD3xCD20 animals, while 4 animals treated with 1 mg/kg of Control III Three of them showed negligible or detectable CD20 signal levels.

In the same experiment, the pharmacokinetic profile of the bispecific antibody (FIG. 7) was assessed by obtaining blood samples pre-dose and at 0.083, 5, 24, 48, 72, 168, 336, 504 and 840 hours. The resulting serum samples were analyzed by direct enzyme-linked immunosorbent assay (ELISA) to determine the concentration of total bispecific antibody. Serum total bispecific (BS3/20-001) concentration data were analyzed by non-compartmental analysis (Phoenix WinNonLin) to determine pharmacokinetic parameters. The results are shown in Table 30 (AUC = area under the curve vs time; C _max = maximum concentration of compound observed in the matrix of interest).

After a single intravenous dose of 0.01, 0.10, or 1.0 mg/kg of BS3/20-001 in cynomolgus monkeys, mean peak concentrations of 0.261, 2.32, and 33.4 μg/mL, respectively, at the first sampling time point (0.083 hr) ( Cmax) was observed. Mean AUC _all values of 4.42, 289, and 4940 μg ^* hr/mL were observed at doses of 0.01, 0.1, and 1.0 mg/kg. Dose-normalized AUC values (AUC _all /dose) of 4.42, 289 and 4940 μg per mg/kg ^* hr/mL indicate that plasma exposure (AUC _all ) increases with increasing dose in a non-linear manner. A greater than proportional increase in plasma drug exposure was observed with increased antibody dose, suggesting that BS3/20-001 may undergo some target-mediated clearance. The overall pharmacokinetic profile of BS3/20-001 is typical of a monoclonal antibody dosed in cynomolgus monkeys.

The present invention should not be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the detailed description for carrying out the invention and the accompanying drawings. Such variations are intended to be within the scope of the claims.

SEQUENCE LISTING <110> REGENERON PHARMACEUTICALS, INC. <120> ANTI-CD3 ANTIBODIES, BISPECIFIC ANTIGEN-BINDING MOLECULES THAT BIND CD3 AND CD20, AND USES THEREOF <130> 9250A-WO <150> US 61/704,029 <151> 2012-09-21 <150> US 61/753,461 <151> 2013-01-17 <150> US 61/763,110 <151> 2013-02-11 <150> US 61/827,098 <151> 2013-05-24 <160> 1375 <170> KopatentIn 1.71 <210> 1 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1 gaagtgcaac tggtggagtc tgggggaggc ttagtacagc ctggcgggtc cctgagactc 60 tcctgtgcag ccactggatt cacctttgat gattttacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt atcagttgga atagtggtag cataggctat 180 gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggccttgt actactgtgc aaaagataat 300 agtggctacg gctattatta ctacggtatg gacgtctggg gccaagggac cacggtcacc 360 gtctcctca 369 <210> 2 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 2 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Thr Gly Phe Thr Phe Asp Asp Phe 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Asn Ser Gly Tyr Gly Tyr Tyr Tyr Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 3 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 3 ggattcacct ttgatgattt tacc 24 <210> 4 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 4 Gly Phe Thr Phe Asp Asp Phe Thr 1 5 <210> 5 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 5 atcagttgga atagtggtag cata 24 <210> 6 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 6 Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <210> 7 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 7 gcaaaagata atagtggcta cggctattat tactacggta tggacgtc 48 <210> 8 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 8 Ala Lys Asp Asn Ser Gly Tyr Gly Tyr Tyr Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 9 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 9 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca cagtgttagc aggaactcag cctggtacca gcagaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180 aggttcagtg gcagtgggtc tgggacagaa ttcactctca ccatcagcag cctgcagtct 240 gaagattttg caattttatta ctgtcagcag tataataatt ggcctctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 10 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 10 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser His Ser Val Ser Arg Asn 20 25 30 Ser Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Ile Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 11 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 11 cacagtgtta gcaggaac 18 <210> 12 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 12 His Ser Val Ser Arg Asn 1 5 <210> 13 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 13 ggtgcatcc 9 <210> 14 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 14 Gly Ala Ser One <210> 15 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 15 cagcagtata ataattggcc tctcact 27 <210> 16 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 16 Gln Gln Tyr Asn Asn Trp Pro Leu Thr 1 5 <210> 17 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 17 gaagtgcaac tggtggaatc ggggggaggc ttggtacagc ctggcgggtc cctgagactc 60 tcctgtgcag cctctggatt ctcctttgat gattatacca tgcactgggt ccggcaacct 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag agctggggac acggccttgt actactgtgc aaaagataat 300 agtggctacg gctattacta ctactacggt atggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 18 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 18 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Gly Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Asn Ser Gly Tyr Gly Tyr Tyr Tyr Tyr Tyr Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 19 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 19 ggattctcct ttgatgatta tacc 24 <210> 20 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 20 Gly Phe Ser Phe Asp Asp Tyr Thr 1 5 <210> 21 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 21 attagttgga attagtggtag cata 24 <210> 22 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 22 Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <210> 23 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 23 gcaaaagata atagtggcta cggctattac tactactacg gtatggacgt c 51 <210> 24 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 24 Ala Lys Asp Asn Ser Gly Tyr Gly Tyr Tyr Tyr Tyr Tyr Gly Met Asp 1 5 10 15 Val <210> 25 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 25 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca gcagaaacct 120 ggccaggctc ccagactcct catctatggt gcatccacca gggccactgg tatcccagcc 180 aggttcagtg gcagtgggtc tgggacagaa ttcactctca ccatcagcag cctgcagtct 240 gaagattttg cagtttatta ctgtcagcag tattataact ggcctctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 26 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 26 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 27 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 27 cagagtgtta gcagcaac 18 <210> 28 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 28 Gln Ser Val Ser Ser Asn 1 5 <210> 29 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 29 ggtgcatcc 9 <210> 30 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 30 Gly Ala Ser One <210> 31 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 31 cagcagtatt ataactggcc tctcact 27 <210> 32 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 32 Gln Gln Tyr Tyr Asn Trp Pro Leu Thr 1 5 <210> 33 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 33 gaagtacagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgtag cctctggatt cccctttgct gattatacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcagat attagttgga atagtggtag caaaggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca atgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag aactgaggac acggccttct attactgtgc aaaagatatg 300 agtggctacg cccactactt ctactacggt atggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 34 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 34 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Pro Phe Ala Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Asn Ser Gly Ser Lys Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Phe Tyr Tyr Cys 85 90 95 Ala Lys Asp Met Ser Gly Tyr Ala His Tyr Phe Tyr Tyr Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 35 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 35 ggattcccct ttgctgatta tacc 24 <210> 36 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 36 Gly Phe Pro Phe Ala Asp Tyr Thr 1 5 <210> 37 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 37 attagttgga attagtggtag caaa 24 <210> 38 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 38 Ile Ser Trp Asn Ser Gly Ser Lys 1 5 <210> 39 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 39 gcaaaagata tgagtggcta cgcccactac ttctactacg gtatggacgt c 51 <210> 40 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 40 Ala Lys Asp Met Ser Gly Tyr Ala His Tyr Phe Tyr Tyr Gly Met Asp 1 5 10 15 Val <210> 41 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 41 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc ggccaagtca gagcattagc agctatttaa attggtttca gcagaaacca 120 gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag agttacagta cccctccgat caccttcggc 300 caagggacac gactggagat taaa 324 <210> 42 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 42 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Pro Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 43 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 43 cagagcatta gcagctat 18 <210> 44 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 44 Gln Ser Ile Ser Ser Tyr 1 5 <210> 45 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 45 gctgcatcc 9 <210> 46 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 46 Ala Ala Ser One <210> 47 <211> 30 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 47 caacagagtt acagtacccc tccgatcacc 30 <210> 48 <211> 10 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 48 Gln Gln Ser Tyr Ser Thr Pro Pro Ile Thr 1 5 10 <210> 49 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 49 gaagtacaac tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctaagactc 60 tcctgtgcag cctctggatt cacctttgat gattatacca tgcactgggt ccggcaagtt 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggcag cttggcctac 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ttccctgtat 240 ctgcaaatga acagtcttca ccctgaggac acggccctct attactgtgt aaaagatggt 300 agtggctacg gccactactc ctactacggt ttggacgtct ggggccaggg gaccacggtc 360 accgtctcct ca 372 <210> 50 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 50 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Leu Ala Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu His Pro Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Val Lys Asp Gly Ser Gly Tyr Gly His Tyr Ser Tyr Tyr Gly Leu Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 51 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 51 ggattcacct ttgatgatta tacc 24 <210> 52 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 52 Gly Phe Thr Phe Asp Asp Tyr Thr 1 5 <210> 53 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 53 attagttgga atagtggcag cttg 24 <210> 54 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 54 Ile Ser Trp Asn Ser Gly Ser Leu 1 5 <210> 55 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 55 gtaaaagatg gtagtggcta cggccactac tcctactacg gtttggacgt c 51 <210> 56 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 56 Val Lys Asp Gly Ser Gly Tyr Gly His Tyr Ser Tyr Tyr Gly Leu Asp 1 5 10 15 Val <210> 57 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 57 gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120 cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180 gacaggttca gtggcagtgg gtctggggaca gacttcactc tcaccatcag cagactggag 240 cctgaagatt ttgcagtgta ttactgtcag cagtatggta gttcaccttg gacgttcggc 300 caagggacca aggtggaaat caaa 324 <210> 58 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 58 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 59 <211> 21 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 59 cagagtgtta gcagcagcta c 21 <210> 60 <211> 7 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 60 Gln Ser Val Ser Ser Ser Tyr 1 5 <210> 61 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 61 ggtgcatcc 9 <210> 62 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 62 Gly Ala Ser One <210> 63 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 63 cagcagtatg gtagttcacc ttggacg 27 <210> 64 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 64 Gln Gln Tyr Gly Ser Ser Pro Trp Thr 1 5 <210> 65 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 65 gaagtacagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgtag cctctggatt cccctttgct gattatacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcagat attagttgga atagtggtag cataggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca atgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag aactgaggac acggccttgt attactgtgc aaaagatatg 300 agtggctacg cccactactt ctactacggt atggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 66 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 66 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Pro Phe Ala Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Met Ser Gly Tyr Ala His Tyr Phe Tyr Tyr Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 67 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 67 ggattcccct ttgctgatta tacc 24 <210> 68 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 68 Gly Phe Pro Phe Ala Asp Tyr Thr 1 5 <210> 69 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 69 attagttgga attagtggtag cata 24 <210> 70 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 70 Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <210> 71 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 71 gcaaaagata tgagtggcta cgcccactac ttctactacg gtatggacgt c 51 <210> 72 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 72 Ala Lys Asp Met Ser Gly Tyr Ala His Tyr Phe Tyr Tyr Gly Met Asp 1 5 10 15 Val <210> 73 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 73 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctttgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag agttacagta cccctccgat caccttcggc 300 caagggacac gactggagat taaa 324 <210> 74 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 74 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Phe Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 75 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 75 cagagcatta gcagctat 18 <210> 76 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 76 Gln Ser Ile Ser Ser Tyr 1 5 <210> 77 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 77 gctgcatcc 9 <210> 78 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 78 Ala Ala Ser One <210> 79 <211> 30 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 79 caacagagtt acagtacccc tccgatcacc 30 <210> 80 <211> 10 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 80 Gln Gln Ser Tyr Ser Thr Pro Pro Ile Thr 1 5 10 <210> 81 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 81 gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgaaactc 60 tcctgtacag cctctggatt cacctttgct gattatacca tgcactgggt ccgacaaggt 120 ccagggaagg gcctggagtg ggtctcagat attagttgga atagtggtag taaaggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag aactgaggac acggccttgt attactgtgc aaaagatatg 300 agtggctacg cccactacta ctactacgct ttggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 82 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 82 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Lys Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ala Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Asn Ser Gly Ser Lys Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Met Ser Gly Tyr Ala His Tyr Tyr Tyr Tyr Ala Leu Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 83 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 83 ggattcacct ttgctgatta tacc 24 <210> 84 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 84 Gly Phe Thr Phe Ala Asp Tyr Thr 1 5 <210> 85 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 85 attagttgga attagtggtag taaa 24 <210> 86 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 86 Ile Ser Trp Asn Ser Gly Ser Lys 1 5 <210> 87 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 87 gcaaaagata tgagtggcta cgcccactac tactactacg ctttggacgt c 51 <210> 88 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 88 Ala Lys Asp Met Ser Gly Tyr Ala His Tyr Tyr Tyr Tyr Ala Leu Asp 1 5 10 15 Val <210> 89 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 89 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gagcattagc aactatttaa attggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag agttacagta accccccgat caccttcggc 300 caagggacac gactggagat taaa 324 <210> 90 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 90 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Asn Pro Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 91 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 91 cagagcatta gcaactat 18 <210> 92 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 92 Gln Ser Ile Ser Asn Tyr 1 5 <210> 93 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 93 gctgcatcc 9 <210> 94 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 94 Ala Ala Ser One <210> 95 <211> 30 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 95 caacagagtt acagtaaccc cccgatcacc 30 <210> 96 <211> 10 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 96 Gln Gln Ser Tyr Ser Asn Pro Pro Ile Thr 1 5 10 <210> 97 <211> 363 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 97 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagt agaaaaggca tgcactgggt ccgccaggct 120 ccagtcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180 gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgac agctgaggac acggctgtgt attactgtgc gaaagaaggg 300 gggcatgact atggtggtac ctttgactac tggggccagg gaaccctggt caccgtctcc 360 tca 363 <210> 98 <211> 121 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 98 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Lys 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Val Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Thr Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Glu Gly Gly His Asp Tyr Gly Gly Thr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 99 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 99 ggattcacct tcagtagaaa aggc 24 <210> 100 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 100 Gly Phe Thr Phe Ser Arg Lys Gly 1 5 <210> 101 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 101 atatcatatg atggaagtaa taaa 24 <210> 102 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 102 Ile Ser Tyr Asp Gly Ser Asn Lys 1 5 <210> 103 <211> 42 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 103 gcgaaagaag gggggcatga ctatggtggt acctttgact ac 42 <210> 104 <211> 14 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 104 Ala Lys Glu Gly Gly His Asp Tyr Gly Gly Thr Phe Asp Tyr 1 5 10 <210> 105 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 105 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc aggcgagtca ggacattaac aactatttaa attggtatca gcagaaacca 120 gggaaagccc ctaagttcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180 aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag cctgcagcct 240 gaagatattg caacatatta ctgtcaacag tatgatgatc tcccattcac tttcggccct 300 gggaccaaag tggatatcaa a 321 <210> 106 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 106 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Asn Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Phe Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asp Leu Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 <210> 107 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 107 caggacatta acaactat 18 <210> 108 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 108 Gln Asp Ile Asn Asn Tyr 1 5 <210> 109 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 109 gatgcatcc 9 <210> 110 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 110 Asp Ala Ser One <210> 111 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 111 caacagtatg atgatctccc attcact 27 <210> 112 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 112 Gln Gln Tyr Asp Asp Leu Pro Phe Thr 1 5 <210> 113 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 113 gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag tataggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa gtccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagataat 300 agtggctacg gtcactacta ctacggaatg gacgtctggg gccaagggac cacggtcacc 360 gtcgcctca 369 <210> 114 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 114 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Asn Ser Gly Tyr Gly His Tyr Tyr Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ala Ser 115 120 <210> 115 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 115 ggattcacct ttgatgatta tacc 24 <210> 116 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 116 Gly Phe Thr Phe Asp Asp Tyr Thr 1 5 <210> 117 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 117 attagttgga attagtggtag tata 24 <210> 118 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 118 Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <210> 119 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 119 gcaaaagata atagtggcta cggtcactac tactacggaa tggacgtc 48 <210> 120 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 120 Ala Lys Asp Asn Ser Gly Tyr Gly His Tyr Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 121 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 121 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca gcaaaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240 gaagattttg cagtttatta ctgtcagcac tatattaact ggcctctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 122 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 122 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Ile Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 123 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 123 cagagtgtta gcagcaac 18 <210> 124 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 124 Gln Ser Val Ser Ser Asn 1 5 <210> 125 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 125 ggtgcatcc 9 <210> 126 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 126 Gly Ala Ser One <210> 127 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 127 cagcactata ttaactggcc tctcact 27 <210> 128 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 128 Gln His Tyr Ile Asn Trp Pro Leu Thr 1 5 <210> 129 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 129 gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag tataggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa gtccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagataat 300 agtggctacg gtcactacta ctacggaatg gacgtctggg gccaagggac cacggtcacc 360 gtcgcctca 369 <210> 130 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 130 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Asn Ser Gly Tyr Gly His Tyr Tyr Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ala Ser 115 120 <210> 131 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 131 ggattcacct ttgatgatta tacc 24 <210> 132 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 132 Gly Phe Thr Phe Asp Asp Tyr Thr 1 5 <210> 133 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 133 attagttgga attagtggtag tata 24 <210> 134 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 134 Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <210> 135 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 135 gcaaaagata atagtggcta cggtcactac tactacggaa tggacgtc 48 <210> 136 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 136 Ala Lys Asp Asn Ser Gly Tyr Gly His Tyr Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 137 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 137 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca gcaaaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240 gaagattttg cagtttatta ctgtcagcac tatattaact ggcctctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 138 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 138 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Ile Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 139 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 139 cagagtgtta gcagcaac 18 <210> 140 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 140 Gln Ser Val Ser Ser Asn 1 5 <210> 141 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 141 ggtgcatcc 9 <210> 142 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 142 Gly Ala Ser One <210> 143 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 143 cagcactata ttaactggcc tctcact 27 <210> 144 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 144 Gln His Tyr Ile Asn Trp Pro Leu Thr 1 5 <210> 145 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 145 caggtgcagt tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtggtg cgtctggatt caccttcaga agttatggca tgcactgggt ccgccagact 120 ccaggcaggg ggctggagtg ggtggcaatg atatattatg atggaaataa taaatactat 180 gcagactccg tgaggggccg attcaccgtt tccagagaca attccaagaa caccctgtat 240 ctgcaaatga gcagcctgag agccgaggac acggctctat atttctgtgc gcgagggcct 300 gggtacaact ggctcgaccc ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 146 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 146 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Gly Ala Ser Gly Phe Thr Phe Arg Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Thr Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ala Met Ile Tyr Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Val Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 147 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 147 ggattcacct tcagaagtta tggc 24 <210> 148 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 148 Gly Phe Thr Phe Arg Ser Tyr Gly 1 5 <210> 149 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 149 atatattatg atggaaataa taaa 24 <210> 150 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 150 Ile Tyr Tyr Asp Gly Asn Asn Lys 1 5 <210> 151 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 151 gcgcgagggc ctgggtacaa ctggctcgac ccc 33 <210> 152 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 152 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro 1 5 10 <210> 153 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 153 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagttatagc aggaacttgg cctggtacca gcaraaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240 gaagattttg cagtttatta ctgtcagcag tataataacc ggcctctcac tttcggcgga 300 gggaccgagg tggagatcaa a 321 <210> 154 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <220> <221> VARIANT <222> 38 <223> Xaa = any amino acid <220> <221> VARIANT <222> 38 <223> Xaa = Any Amino Acid <400> 154 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Arg Asn 20 25 30 Leu Ala Trp Tyr Gln Xaa Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Arg Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys 100 105 <210> 155 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 155 cagagtatta gcaggaac 18 <210> 156 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 156 Gln Ser Ile Ser Arg Asn 1 5 <210> 157 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 157 ggtgcatcc 9 <210> 158 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 158 Gly Ala Ser One <210> 159 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 159 cagcagtata ataaccggcc tctcact 27 <210> 160 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 160 Gln Gln Tyr Asn Asn Arg Pro Leu Thr 1 5 <210> 161 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 161 caggtgcagt tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 gcctgtgttg cgtctggatt caccttcaga agttatggca tgcactgggt ccgccaggct 120 ccaggcaagg gactgcagtg ggtggcaatg atttactatg atggtaagaa taaatattat 180 gcagactccg tgaggggccg attcaccatc tccagagaca attccaagaa cacactgtat 240 ctgcaaatga acaatctgag agtcgaggac acggctatgt atttctgtgc gcgagggcct 300 gggtacaatt ggctcgaccc ctggggccag ggaaccctgg tcactgtttc ctca 354 <210> 162 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 162 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ala Cys Val Ala Ser Gly Phe Thr Phe Arg Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Gln Trp Val 35 40 45 Ala Met Ile Tyr Tyr Asp Gly Lys Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Asn Leu Arg Val Glu Asp Thr Ala Met Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 163 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 163 ggattcacct tcagaagtta tggc 24 <210> 164 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 164 Gly Phe Thr Phe Arg Ser Tyr Gly 1 5 <210> 165 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 165 atttactatg atggtaagaa taaa 24 <210> 166 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 166 Ile Tyr Tyr Asp Gly Lys Asn Lys 1 5 <210> 167 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 167 gcgcgagggc ctgggtacaa ttggctcgac ccc 33 <210> 168 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 168 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro 1 5 10 <210> 169 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 169 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagaattagc agcaacttgg cctggtacca gcaaaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tagcccagcc 180 aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctgcagtct 240 gaggatgttg cagtttatta ctgtcagcaa catcataact ggcctctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 170 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 170 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Arg Ile Ser Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ser Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Val Ala Val Tyr Cys Gln Gln His His Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 171 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 171 cagagaatta gcagcaac 18 <210> 172 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 172 Gln Arg Ile Ser Ser Asn 1 5 <210> 173 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 173 ggtgcatcc 9 <210> 174 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 174 Gly Ala Ser One <210> 175 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 175 cagcaacatc ataactggcc tctcact 27 <210> 176 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 176 Gln Gln His His Asn Trp Pro Leu Thr 1 5 <210> 177 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 177 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgctg cgtctggatt taccttcaga agttatgcca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcaatg gtatactatg atggaaataa tcaatactat 180 gcagactccg tgaggggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agccgatgac acggctgtgt atttctgtgc gcgagggcct 300 gggtacaact ggctcgaccc ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 178 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 178 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Met Val Tyr Tyr Asp Gly Asn Asn Gln Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 179 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 179 ggatttacct tcagaagtta tgcc 24 <210> 180 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 180 Gly Phe Thr Phe Arg Ser Tyr Ala 1 5 <210> 181 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 181 gtatactatg atggaaataa tcaa 24 <210> 182 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 182 Val Tyr Tyr Asp Gly Asn Asn Gln 1 5 <210> 183 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 183 gcgcgagggc ctgggtacaa ctggctcgac ccc 33 <210> 184 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 184 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro 1 5 10 <210> 185 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 185 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc aggaacttgg cctggtacca gcaaaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccggcc 180 aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctgcagtct 240 gaagattttg cagtttatta ctgtcagcag tataataact ggcctctcac tttcggcgga 300 gggaccaagg tggtgatcaa a 321 <210> 186 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 186 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Val Ile Lys 100 105 <210> 187 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 187 cagagtgtta gcaggaac 18 <210> 188 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 188 Gln Ser Val Ser Arg Asn 1 5 <210> 189 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 189 ggtgcatcc 9 <210> 190 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 190 Gly Ala Ser One <210> 191 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 191 cagcagtata ataactggcc tctcact 27 <210> 192 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 192 Gln Gln Tyr Asn Asn Trp Pro Leu Thr 1 5 <210> 193 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 193 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtattg cgtctggatt taccttcaga agttatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcaatg atatattatg atggaaacaa taaatactat 180 gcagactccg tgaggggccg attcaccatc tccagagaca actccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agccgatgac acggctgtgt atttctgtgc gcgagggcct 300 gggtacaact ggctcgaccc ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 194 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 194 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ile Ala Ser Gly Phe Thr Phe Arg Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Met Ile Tyr Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 195 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 195 ggatttacct tcagaagtta tggc 24 <210> 196 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 196 Gly Phe Thr Phe Arg Ser Tyr Gly 1 5 <210> 197 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 197 atatattatg atggaaacaa taaa 24 <210> 198 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 198 Ile Tyr Tyr Asp Gly Asn Asn Lys 1 5 <210> 199 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 199 gcgcgagggc ctgggtacaa ctggctcgac ccc 33 <210> 200 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 200 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro 1 5 10 <210> 201 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 201 gaaatagtga tgacgcagtc tccagccaca ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc agcaacttgg cctggtacca gcagaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240 gaagattttg cagtttatta ctgtcagcag tataataaca ggcctctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 202 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 202 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Arg Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 203 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 203 cagagtgtta gcagcaac 18 <210> 204 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 204 Gln Ser Val Ser Ser Asn 1 5 <210> 205 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 205 ggtgcatcc 9 <210> 206 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 206 Gly Ala Ser One <210> 207 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 207 cagcagtata ataacaggcc tctcact 27 <210> 208 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 208 Gln Gln Tyr Asn Asn Arg Pro Leu Thr 1 5 <210> 209 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 209 caggtgcagc tggtggagtc tgggggaggc gtggtccagc cggggaggtc cctgagactc 60 tcctgtgctg cgtctggatt caccttcaga agttttggca tgcactgggt ccgccaggct 120 ccaggcaggg gactggagtg ggtggcaatg atatattttg atggaaaaaa taaatactat 180 gcagactccg tgaggggccg attcaccatt tccagagaca attccaagaa caccctgtat 240 ctggaaatga gtagcctgag agccgaggac acggctgtat atttctgtgc gcgagggcct 300 gggtacaact ggctcgaccc ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 210 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 210 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ala Met Ile Tyr Phe Asp Gly Lys Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Glu Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 211 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 211 ggattcacct tcagaagttt tggc 24 <210> 212 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 212 Gly Phe Thr Phe Arg Ser Phe Gly 1 5 <210> 213 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 213 atatattttg atggaaaaaa taaa 24 <210> 214 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 214 Ile Tyr Phe Asp Gly Lys Asn Lys 1 5 <210> 215 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 215 gcgcgagggc ctgggtacaa ctggctcgac ccc 33 <210> 216 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 216 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro 1 5 10 <210> 217 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 217 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagtcacc 60 ctctcctgta gggccagtca gagttatagc aggaacttgg cctggtacca gcagaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tgtcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctacagtct 240 gaagattttg cagtttttca ctgtcagcag tataataata ggcctctcac tttcggcgga 300 gggaccgagg tggagatcaa a 321 <210> 218 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 218 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Arg Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Phe His Cys Gln Gln Tyr Asn Asn Arg Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys 100 105 <210> 219 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 219 cagagtatta gcaggaac 18 <210> 220 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 220 Gln Ser Ile Ser Arg Asn 1 5 <210> 221 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 221 ggtgcatcc 9 <210> 222 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 222 Gly Ala Ser One <210> 223 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 223 cagcagtata ataataggcc tctcact 27 <210> 224 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 224 Gln Gln Tyr Asn Asn Arg Pro Leu Thr 1 5 <210> 225 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 225 caggtgcaat tggtggagtc tgggggaggc gtggtccagc cggggaggtc cctgagactc 60 tcctgtgctg cgtctggatt caccttcaga agttttggca tgcactgggt ccgccaggct 120 ccaggcaggg gactggagtg ggtggcaatg atatattttg atggaaaaaa taaatactat 180 gcagactccg tgaggggccg attcaccatt tccagagaca attccaagaa caccctgtat 240 ctggaaatga gtagcctgag agccgaggac acggctgtat atttctgtgc gcgagggcct 300 gggtacaact ggctcgaccc ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 226 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 226 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ala Met Ile Tyr Phe Asp Gly Lys Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Glu Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 227 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 227 ggattcacct tcagaagttt tggc 24 <210> 228 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 228 Gly Phe Thr Phe Arg Ser Phe Gly 1 5 <210> 229 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 229 atatattttg atggaaaaaa taaa 24 <210> 230 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 230 Ile Tyr Phe Asp Gly Lys Asn Lys 1 5 <210> 231 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 231 gcgcgagggc ctgggtacaa ctggctcgac ccc 33 <210> 232 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 232 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro 1 5 10 <210> 233 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 233 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagtcacc 60 ctctcctgta gggccagtca gagttatagc aggaacttgg cctggtacca gcaraaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tgtcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctacagtct 240 gaagattttg cagtttttca ctgtcagcag tataataata ggcctctcac tttcggcgga 300 gggaccgagg tggagatcaa a 321 <210> 234 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <220> <221> VARIANT <222> 38 <223> Xaa = Any amino acid <220> <221> VARIANT <222> 38 <223> Xaa = Any Amino Acid <400> 234 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Arg Asn 20 25 30 Leu Ala Trp Tyr Gln Xaa Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Phe His Cys Gln Gln Tyr Asn Asn Arg Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys 100 105 <210> 235 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 235 cagagtatta gcaggaac 18 <210> 236 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 236 Gln Ser Ile Ser Arg Asn 1 5 <210> 237 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 237 ggtgcatcc 9 <210> 238 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 238 Gly Ala Ser One <210> 239 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 239 cagcagtata ataataggcc tctcact 27 <210> 240 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 240 Gln Gln Tyr Asn Asn Arg Pro Leu Thr 1 5 <210> 241 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 241 caggtgcaat tggtggagtc tgggggaggc gtggtccagc cggggaggtc cctgagactc 60 tcctgtgctg cgtctggatt caccttcaga agttttggca tgcactgggt ccgccaggct 120 ccaggcaggg gactggagtg ggtggcaatg atatattttg atggaaaaaa taaatactat 180 gcagactccg tgaggggccg attcaccatt tccagagaca attccaagaa caccctgtat 240 ctggaaatga gcagcctgag agccgaggac acggctgtat atttctgtgc gcgagggcct 300 gggtacaatt ggctcgaccc ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 242 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 242 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ala Met Ile Tyr Phe Asp Gly Lys Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Glu Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 243 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 243 ggattcacct tcagaagttt tggc 24 <210> 244 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 244 Gly Phe Thr Phe Arg Ser Phe Gly 1 5 <210> 245 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 245 atatattttg atggaaaaaa taaa 24 <210> 246 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 246 Ile Tyr Phe Asp Gly Lys Asn Lys 1 5 <210> 247 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 247 gcgcgagggc ctgggtacaa ttggctcgac ccc 33 <210> 248 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 248 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro 1 5 10 <210> 249 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 249 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgta gggccagtca gagtgttagc aggaacttgg cctggtacca gcaaaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tgtcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctacagtct 240 gaagattttg cagtttttca ctgtcagcag tataataata ggcctctcac tttcggcgga 300 gggaccgagg tggagatcaa a 321 <210> 250 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 250 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Phe His Cys Gln Gln Tyr Asn Asn Arg Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys 100 105 <210> 251 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 251 cagagtgtta gcaggaac 18 <210> 252 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 252 Gln Ser Val Ser Arg Asn 1 5 <210> 253 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 253 ggtgcatcc 9 <210> 254 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 254 Gly Ala Ser One <210> 255 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 255 cagcagtata ataataggcc tctcact 27 <210> 256 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 256 Gln Gln Tyr Asn Asn Arg Pro Leu Thr 1 5 <210> 257 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 257 caggtgcaat tggtggagtc tgggggaggc gtggtccagc cggggaggtc cctgagactc 60 tcctgtgctg cgtctggatt caccttcaga agttttggca tgcactgggt ccgccaggct 120 ccaggcaggg gactggagtg ggtggcaatg atatattttg atggaaaaaa taaatactat 180 gcagactccg tgaggggccg attcaccatt tccagagaca attccaagaa caccctgtat 240 ctggaaatga gcagcctgag agccgaggac acggctgtat atttctgtgc gcgagggcct 300 gggtacaatt ggctcgaccc ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 258 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 258 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ala Met Ile Tyr Phe Asp Gly Lys Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Glu Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 259 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 259 ggattcacct tcagaagttt tggc 24 <210> 260 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 260 Gly Phe Thr Phe Arg Ser Phe Gly 1 5 <210> 261 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 261 atatattttg atggaaaaaa taaa 24 <210> 262 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 262 Ile Tyr Phe Asp Gly Lys Asn Lys 1 5 <210> 263 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 263 gcgcgagggc ctgggtacaa ttggctcgac ccc 33 <210> 264 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 264 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro 1 5 10 <210> 265 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 265 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgta gggccagtca gagtgttagc aggaacttgg cctggtacca gcaaaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tgtcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctacagtct 240 gaagattttg cagtttttca ctgtcagcag tataataata ggcctctcac tttcggcgga 300 gggaccgagg tggagatcaa a 321 <210> 266 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 266 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Phe His Cys Gln Gln Tyr Asn Asn Arg Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys 100 105 <210> 267 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 267 cagagtgtta gcaggaac 18 <210> 268 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 268 Gln Ser Val Ser Arg Asn 1 5 <210> 269 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 269 ggtgcatcc 9 <210> 270 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 270 Gly Ala Ser One <210> 271 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 271 cagcagtata ataataggcc tctcact 27 <210> 272 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 272 Gln Gln Tyr Asn Asn Arg Pro Leu Thr 1 5 <210> 273 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 273 caggtgcagt tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgttg cgtctggatt caccttcaga agttatggca tgcactgggt ccgccaggct 120 ccaggcaagg gactgcagtg ggtggcaatg atttactatg atggtaagaa taaatattat 180 gcagactccg tgaggggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagtctgag agccgaagac acggctatgt atttctgtgc gcgagggcct 300 gggtacaact ggctcgaccc ctggggccag ggaaccctgg tcactgtctc ctca 354 <210> 274 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 274 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Arg Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Gln Trp Val 35 40 45 Ala Met Ile Tyr Tyr Asp Gly Lys Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 275 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 275 ggattcacct tcagaagtta tggc 24 <210> 276 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 276 Gly Phe Thr Phe Arg Ser Tyr Gly 1 5 <210> 277 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 277 atttactatg atggtaagaa taaa 24 <210> 278 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 278 Ile Tyr Tyr Asp Gly Lys Asn Lys 1 5 <210> 279 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 279 gcgcgagggc ctgggtacaa ctggctcgac ccc 33 <210> 280 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 280 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro 1 5 10 <210> 281 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 281 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagaattagc agcaacttgg cctggtacca gcaaaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tagcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240 gaagatgttg cagtttatta ctgtcagcaa cataataact ggcctctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 282 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 282 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Arg Ile Ser Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ser Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Val Ala Val Tyr Cys Gln Gln His Asn Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 283 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 283 cagagaatta gcagcaac 18 <210> 284 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 284 Gln Arg Ile Ser Ser Asn 1 5 <210> 285 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 285 ggtgcatcc 9 <210> 286 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 286 Gly Ala Ser One <210> 287 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 287 cagcaacata ataactggcc tctcact 27 <210> 288 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 288 Gln Gln His Asn Asn Trp Pro Leu Thr 1 5 <210> 289 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 289 caggtgcaat tggtggagtc tgggggaggc gtggtccagc cggggaggtc cctgagactc 60 tcctgtgctg cgtctggttt caccttcaga agttttggca tgcactgggt ccgccaggct 120 ccaggcaggg gactggagtg ggtggcaatg atatattttg atggaaaaaa taaatactat 180 gcagactccg tgaggggccg attcaccatt tccagagaca attccaagaa caccctgtat 240 ctggaaatga gtagcctgag agccgaggac acggctgtat atttctgtgc gcgagggcct 300 gggtacaact ggctcgaccc ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 290 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 290 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ala Met Ile Tyr Phe Asp Gly Lys Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Glu Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 291 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 291 ggtttcacct tcagaagttt tggc 24 <210> 292 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 292 Gly Phe Thr Phe Arg Ser Phe Gly 1 5 <210> 293 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 293 atatattttg atggaaaaaa taaa 24 <210> 294 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 294 Ile Tyr Phe Asp Gly Lys Asn Lys 1 5 <210> 295 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 295 gcgcgagggc ctgggtacaa ctggctcgac ccc 33 <210> 296 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 296 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro 1 5 10 <210> 297 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 297 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagtcatc 60 ctctcctgta gggccagtca gagttatagc aggaacttgg cctggtacca gcaaaaacct 120 ggccaggctc ccaggctcct catctatggt gcaaccacca gggccactgg tgtcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctacagtct 240 gaagattttg cagtttttta ctgtcagcag tataataata ggcctctcac tttcggcgga 300 gggaccgagg tggagatcaa a 321 <210> 298 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 298 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ile Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Arg Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Thr Thr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Phe Tyr Cys Gln Gln Tyr Asn Asn Arg Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys 100 105 <210> 299 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 299 cagagtatta gcaggaac 18 <210> 300 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 300 Gln Ser Ile Ser Arg Asn 1 5 <210> 301 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 301 ggtgcaacc 9 <210> 302 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 302 Gly Ala Thr One <210> 303 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 303 cagcagtata ataataggcc tctcact 27 <210> 304 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 304 Gln Gln Tyr Asn Asn Arg Pro Leu Thr 1 5 <210> 305 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 305 caggtgcaat tggtggagtc tgggggaggc gtggtccagc cggggaggtc cctgagactc 60 tcctgtgctg cgtctggttt caccttcaga agttttggca tgcactgggt ccgccaggct 120 ccaggcaggg gactggagtg ggtggcaatg atatattttg atggaaaaaa taaatactat 180 gcagactccg tgaggggccg attcaccatt tccagagaca attccaagaa caccctgtat 240 ctggaaatga gtagcctgag agccgaggac acggctgtat atttctgtgc gcgagggcct 300 gggtacaact ggctcgaccc ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 306 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 306 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ala Met Ile Tyr Phe Asp Gly Lys Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Glu Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 307 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 307 ggtttcacct tcagaagttt tggc 24 <210> 308 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 308 Gly Phe Thr Phe Arg Ser Phe Gly 1 5 <210> 309 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 309 atatattttg atggaaaaaa taaa 24 <210> 310 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 310 Ile Tyr Phe Asp Gly Lys Asn Lys 1 5 <210> 311 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 311 gcgcgagggc ctgggtacaa ctggctcgac ccc 33 <210> 312 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 312 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro 1 5 10 <210> 313 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 313 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagtcatc 60 ctctcctgta gggccagtca gagttatagc aggaacttgg cctggtacca gcaraaacct 120 ggccaggctc ccaggctcct catctatggt gcaaccacca gggccactgg tgtcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctacagtct 240 gaagattttg cagtttttta ctgtcagcag tataataata ggcctctcac tttcggcgga 300 gggaccgagg tggagatcaa a 321 <210> 314 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <220> <221> VARIANT <222> 38 <223> Xaa = Any amino acid <220> <221> VARIANT <222> 38 <223> Xaa = Any Amino Acid <400> 314 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ile Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Arg Asn 20 25 30 Leu Ala Trp Tyr Gln Xaa Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Thr Thr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Phe Tyr Cys Gln Gln Tyr Asn Asn Arg Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys 100 105 <210> 315 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 315 cagagtatta gcaggaac 18 <210> 316 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 316 Gln Ser Ile Ser Arg Asn 1 5 <210> 317 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 317 ggtgcaacc 9 <210> 318 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 318 Gly Ala Thr One <210> 319 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 319 cagcagtata ataataggcc tctcact 27 <210> 320 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 320 Gln Gln Tyr Asn Asn Arg Pro Leu Thr 1 5 <210> 321 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 321 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtattg cgtctggatt taccttcaga agttatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcaatg atatattatg atggaaacaa taaatactat 180 gcagactccg tgaggggccg attcaccatc tccagagaca actccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agccgatgac acggctgtgt atttctgtgc gcgagggcct 300 gggtacaact ggctcgaccc ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 322 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 322 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ile Ala Ser Gly Phe Thr Phe Arg Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Met Ile Tyr Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 323 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 323 ggatttacct tcagaagtta tggc 24 <210> 324 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 324 Gly Phe Thr Phe Arg Ser Tyr Gly 1 5 <210> 325 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 325 atatattatg atggaaacaa taaa 24 <210> 326 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 326 Ile Tyr Tyr Asp Gly Asn Asn Lys 1 5 <210> 327 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 327 gcgcgagggc ctgggtacaa ctggctcgac ccc 33 <210> 328 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 328 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro 1 5 10 <210> 329 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 329 gaaatagtga tgacgcagtc tccagccaca ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc agcaacttgg cctggtacca gcagaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240 gaagattttg cagtttatta ctgtcagcag tataataaca ggcctctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 330 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 330 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Arg Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 331 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 331 cagagtgtta gcagcaac 18 <210> 332 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 332 Gln Ser Val Ser Ser Asn 1 5 <210> 333 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 333 ggtgcatcc 9 <210> 334 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 334 Gly Ala Ser One <210> 335 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 335 cagcagtata ataacaggcc tctcact 27 <210> 336 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 336 Gln Gln Tyr Asn Asn Arg Pro Leu Thr 1 5 <210> 337 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 337 gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattattcca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtcgtag catagactat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgt aaaagataat 300 agtggctatg gccgctatta ctactacggg atggacgtct ggggccaagg gaccacggtc 360 tccgtctcct ca 372 <210> 338 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 338 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Arg Ser Ile Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Val Lys Asp Asn Ser Gly Tyr Gly Arg Tyr Tyr Tyr Tyr Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Ser Val Ser Ser 115 120 <210> 339 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 339 ggattcacct ttgatgatta ttcc 24 <210> 340 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 340 Gly Phe Thr Phe Asp Asp Tyr Ser 1 5 <210> 341 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 341 attagttgga atagtcgtag cata 24 <210> 342 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 342 Ile Ser Trp Asn Ser Arg Ser Ile 1 5 <210> 343 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 343 gtaaaagata atagtggcta tggccgctat tactactacg ggatggacgt c 51 <210> 344 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 344 Val Lys Asp Asn Ser Gly Tyr Gly Arg Tyr Tyr Tyr Tyr Gly Met Asp 1 5 10 15 Val <210> 345 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 345 aaaatagtga tgacgcagtc tcccgccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc ggcaacttag cctggtacca gcaaaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactag tatcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240 gaagattttg cagtttattt ctgtcagcac tattataact ggcctctcac tttcggcgga 300 gggaccaagg tggagatcag a 321 <210> 346 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 346 Lys Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Ser Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Phe Cys Gln His Tyr Tyr Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Arg 100 105 <210> 347 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 347 cagagtgtta gcggcaac 18 <210> 348 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 348 Gln Ser Val Ser Gly Asn 1 5 <210> 349 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 349 ggtgcatcc 9 <210> 350 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 350 Gly Ala Ser One <210> 351 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 351 cagcactatt ataactggcc tctcact 27 <210> 352 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 352 Gln His Tyr Tyr Asn Trp Pro Leu Thr 1 5 <210> 353 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 353 gaagtgcaac tggtggagtc tgggggaggc ttagtacagc ctggcgggtc cctgagactc 60 tcctgtgcag ccactggatt cacctttgat gattttacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt atcagttgga atagtggtag cataggctat 180 gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggccttgt actactgtgc aaaagataat 300 agtggctacg gctattatta ctacggtatg gacgtctggg gccaagggac cacggtcacc 360 gtctcctca 369 <210> 354 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 354 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Thr Gly Phe Thr Phe Asp Asp Phe 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Asn Ser Gly Tyr Gly Tyr Tyr Tyr Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 355 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 355 ggattcacct ttgatgattt tacc 24 <210> 356 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 356 Gly Phe Thr Phe Asp Asp Phe Thr 1 5 <210> 357 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 357 atcagttgga atagtggtag cata 24 <210> 358 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 358 Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <210> 359 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 359 gcaaaagata atagtggcta cggctattat tactacggta tggacgtc 48 <210> 360 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 360 Ala Lys Asp Asn Ser Gly Tyr Gly Tyr Tyr Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 361 <211> 339 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 361 gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60 atcaactgca agtccagcca gagtgtttta tacagctcca acaataagaa ctacttagct 120 tggtaccagc agaaaccagg acagcctcct aagctgctca tttactgggc atctacccgg 180 gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240 atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatagtact 300 ccgtacactt ttggccaggg gaccaagctg gagatcaaa 339 <210> 362 <211> 113 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 362 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 100 105 110 Lys <210> 363 <211> 36 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 363 cagagtgttt tatacagctc caacaataag aactac 36 <210> 364 <211> 12 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 364 Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr 1 5 10 <210> 365 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 365 tgggcatct 9 <210> 366 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 366 Trp Ala Ser One <210> 367 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 367 cagcaatatt atagtactcc gtacact 27 <210> 368 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 368 Gln Gln Tyr Tyr Ser Thr Pro Tyr Thr 1 5 <210> 369 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 369 caggtcacct tgaaggagtc tggtcctgcg ctggtgaaac ccacacagac cctcacactg 60 acctgcacct tctctgggtt ctcactcagc actagtggaa tgtgtgtgag ctggatccgt 120 cagcccccag ggaaggccct ggagtggctt gcacgcattg attgggatga tgataaatac 180 tacagcacat ctctgaagac caggctcacc atctccaagg acacctccaa aaaccaggtg 240 gtccttacaa tgaccaacat ggaccctgtg gacacagcca cgtattactg tgcacggatg 300 gatatagtgg gagctagagg ggggtggttc gacccctggg gccagggaac cctggtcacc 360 gtctcctca 369 <210> 370 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 370 Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Cys Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala Arg Ile Asp Trp Asp Asp Asp Lys Tyr Tyr Ser Thr Ser 50 55 60 Leu Lys Thr Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Met Asp Ile Val Gly Ala Arg Gly Gly Trp Phe Asp Pro 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 371 <211> 30 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 371 gggttctcac tcagcactag tggaatgtgt 30 <210> 372 <211> 10 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 372 Gly Phe Ser Leu Ser Thr Ser Gly Met Cys 1 5 10 <210> 373 <211> 21 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 373 attgattggg atgatgataa a 21 <210> 374 <211> 7 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 374 Ile Asp Trp Asp Asp Asp Lys 1 5 <210> 375 <211> 45 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 375 gcacggatgg atatagtggg agctagaggg gggtggttcg acccc 45 <210> 376 <211> 15 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 376 Ala Arg Met Asp Ile Val Gly Ala Arg Gly Gly Trp Phe Asp Pro 1 5 10 15 <210> 377 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 377 gacatccaga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc gggcgagtca gggcattagc aattatttag cctggtttca gcagaaacca 120 gggaaagccc ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aagttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaagattttg caacttatta ctgccaacag tataatagtt acccgctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 378 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 378 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30 Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 379 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 379 cagggcatta gcaattat 18 <210> 380 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 380 Gln Gly Ile Ser Asn Tyr 1 5 <210> 381 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 381 gctgcatcc 9 <210> 382 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 382 Ala Ala Ser One <210> 383 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 383 caacagtata atagttaccc gctcact 27 <210> 384 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 384 Gln Gln Tyr Asn Ser Tyr Pro Leu Thr 1 5 <210> 385 <211> 404 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 385 caggtgcagt tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgctg cgtctggatt caccttcaga agttatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcaatg atatattatg atggaaataa taaaaagtat 180 gcagactccg tgaggggccg attcaccatt tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agtcgaggac acggctgtgt atttctgtgc gcgagggcct 300 gggtacaact ggctcgaccc ctggggccag ggaaccctgg tcaccgtctc ctcagccaaa 360 acaacagccc cacccgttta tccactggcc cctggaagct tggg 404 <210> 386 <211> 134 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 386 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Met Ile Tyr Tyr Asp Gly Asn Asn Lys Lys Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Lys Thr Thr Ala Pro Pro Val Tyr Pro 115 120 125 Leu Ala Pro Gly Ser Leu 130 <210> 387 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 387 ggattcacct tcagaagtta tggc 24 <210> 388 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 388 Gly Phe Thr Phe Arg Ser Tyr Gly 1 5 <210> 389 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 389 atatattatg atggaaataa taaa 24 <210> 390 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 390 Ile Tyr Tyr Asp Gly Asn Asn Lys 1 5 <210> 391 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 391 gcgcgagggc ctgggtacaa ctggctcgac ccc 33 <210> 392 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 392 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro 1 5 10 <210> 393 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 393 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc aggaacttgg cctggtacca gcagaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactga tatcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcattctca acatcagcag cctgcagtct 240 gaagattttg cactttatta ctgtcaacaa tatagtaact ggcctctcac tttcggcgga 300 gggaccgagg tggagatcaa a 321 <210> 394 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 394 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Asp Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Ile Leu Asn Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Leu Tyr Tyr Cys Gln Gln Tyr Ser Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys 100 105 <210> 395 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 395 cagagtgtta gcaggaac 18 <210> 396 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 396 Gln Ser Val Ser Arg Asn 1 5 <210> 397 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 397 ggtgcatcc 9 <210> 398 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 398 Gly Ala Ser One <210> 399 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 399 caacaatata gtaactggcc tctcact 27 <210> 400 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 400 Gln Gln Tyr Ser Asn Trp Pro Leu Thr 1 5 <210> 401 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 401 caggtgcaat tggtggagtc tgggggaggc gtggtccagc cggggaggtc cctgagactc 60 tcctgtgctg cgtctggttt caccttcaga agttttggca tgcactgggt ccgccaggct 120 ccaggcaggg gactggagtg ggtggcaatg atatattttg atggaaaaaa taaatactat 180 gcagactccg tgaggggccg attcaccatt tccagagaca attccaagaa caccctgtat 240 ctggaaatga gtagcctgag agccgaggac acggctgtat atttctgtgc gcgagggcct 300 gggtacaact ggctcgaccc ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 402 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 402 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ala Met Ile Tyr Phe Asp Gly Lys Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Glu Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 403 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 403 ggtttcacct tcagaagttt tggc 24 <210> 404 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 404 Gly Phe Thr Phe Arg Ser Phe Gly 1 5 <210> 405 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 405 atatattttg atggaaaaaa taaa 24 <210> 406 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 406 Ile Tyr Phe Asp Gly Lys Asn Lys 1 5 <210> 407 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 407 gcgcgagggc ctgggtacaa ctggctcgac ccc 33 <210> 408 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 408 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro 1 5 10 <210> 409 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 409 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagtcatc 60 ctctcctgta gggccagtca gagttatagc aggaacttgg cctggtacca gcagaaacct 120 ggccaggctc ccaggctcct catctatggt gcaaccacca gggccactgg tgtcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctacagtct 240 gaagattttg cagtttttta ctgtcagcag tataataata ggcctctcac tttcggcgga 300 gggaccgagg tggagatcaa a 321 <210> 410 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 410 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ile Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Arg Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Thr Thr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Phe Tyr Cys Gln Gln Tyr Asn Asn Arg Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys 100 105 <210> 411 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 411 cagagtatta gcaggaac 18 <210> 412 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 412 Gln Ser Ile Ser Arg Asn 1 5 <210> 413 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 413 ggtgcaacc 9 <210> 414 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 414 Gly Ala Thr One <210> 415 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 415 cagcagtata ataataggcc tctcact 27 <210> 416 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 416 Gln Gln Tyr Asn Asn Arg Pro Leu Thr 1 5 <210> 417 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 417 caggtgcaat tggtggagtc tgggggaggc gtggtccagc cggggaggtc cctgagactc 60 tcctgtgctg cgtctggttt caccttcaga agttttggca tgcactgggt ccgccaggct 120 ccaggcaggg gactggagtg ggtggcaatg atatattttg atggaaaaaa taaatactat 180 gcagactccg tgaggggccg attcaccatt tccagagaca attccaagaa caccctgtat 240 ctggaaatga gtagcctgag agccgaggac acggctgtat atttctgtgc gcgagggcct 300 gggtacaact ggctcgaccc ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 418 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 418 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ala Met Ile Tyr Phe Asp Gly Lys Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Glu Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 419 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 419 ggtttcacct tcagaagttt tggc 24 <210> 420 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 420 Gly Phe Thr Phe Arg Ser Phe Gly 1 5 <210> 421 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 421 atatattttg atggaaaaaa taaa 24 <210> 422 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 422 Ile Tyr Phe Asp Gly Lys Asn Lys 1 5 <210> 423 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 423 gcgcgagggc ctgggtacaa ctggctcgac ccc 33 <210> 424 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 424 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro 1 5 10 <210> 425 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 425 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagtcatc 60 ctctcctgta gggccagtca gagttatagc aggaacttgg cctggtacca gcagaaacct 120 ggccaggctc ccaggctcct catctatggt gcaaccacca gggccactgg tgtcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctacagtct 240 gaagattttg cagtttttta ctgtcagcag tataataata ggcctctcac tttcggcgga 300 gggaccgagg tggagatcaa a 321 <210> 426 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 426 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ile Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Arg Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Thr Thr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Phe Tyr Cys Gln Gln Tyr Asn Asn Arg Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys 100 105 <210> 427 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 427 cagagtatta gcaggaac 18 <210> 428 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 428 Gln Ser Ile Ser Arg Asn 1 5 <210> 429 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 429 ggtgcaacc 9 <210> 430 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 430 Gly Ala Thr One <210> 431 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 431 cagcagtata ataataggcc tctcact 27 <210> 432 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 432 Gln Gln Tyr Asn Asn Arg Pro Leu Thr 1 5 <210> 433 <211> 351 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 433 caggtgcacc tggaagagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgttcag cgtctggttt caccttcagt agttatgcca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaactaa taaatattat 180 ttagattccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgttt 240 ctgcaaatga acagcctgag agccgaagac acggctgtgt attactgtgc gagagatcgg 300 ggaagtataa taacccactg gggccaggga accctggtca ccgtctcctc a 351 <210> 434 <211> 117 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 434 Gln Val His Leu Glu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Thr Asn Lys Tyr Tyr Leu Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Gly Ser Ile Ile Thr His Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 435 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 435 ggtttcacct tcagtagtta tgcc 24 <210> 436 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 436 Gly Phe Thr Phe Ser Ser Tyr Ala 1 5 <210> 437 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 437 atatggtatg atggaactaa taaa 24 <210> 438 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 438 Ile Trp Tyr Asp Gly Thr Asn Lys 1 5 <210> 439 <211> 30 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 439 gcgagagatc ggggaagtat aataacccac 30 <210> 440 <211> 10 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 440 Ala Arg Asp Arg Gly Ser Ile Ile Thr His 1 5 10 <210> 441 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 441 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctataggaga cagagtcacc 60 atcacttgcc gggcaagtca gaacattagc agctatttaa attggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag acttacagta cccctccgat caccttcggc 300 caagggacac gactggagat taaa 324 <210> 442 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 442 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ile Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Tyr Ser Thr Pro Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 443 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 443 cagaacatta gcagctat 18 <210> 444 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 444 Gln Asn Ile Ser Ser Tyr 1 5 <210> 445 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 445 gctgcatcc 9 <210> 446 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 446 Ala Ala Ser One <210> 447 <211> 30 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 447 caacagactt acagtacccc tccgatcacc 30 <210> 448 <211> 10 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 448 Gln Gln Thr Tyr Ser Thr Pro Pro Ile Thr 1 5 10 <210> 449 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 449 gaagtacagc tggtggagtc tgggggaggc ttggtacggc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatacca tgcactgggt ccgccaagct 120 ccagggaagg gcctggagtg ggtctcagat attagttgga atagtggggac cataggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag acctgaggac acggccttgt attactgtgc aaaagatatg 300 agtggctacg cccactacta ctactacggt atggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 450 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 450 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Asn Ser Gly Thr Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Met Ser Gly Tyr Ala His Tyr Tyr Tyr Tyr Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 451 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 451 ggattcacct ttgatgatta tacc 24 <210> 452 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 452 Gly Phe Thr Phe Asp Asp Tyr Thr 1 5 <210> 453 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 453 attagttgga atagtgggac cata 24 <210> 454 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 454 Ile Ser Trp Asn Ser Gly Thr Ile 1 5 <210> 455 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 455 gcaaaagata tgagtggcta cgcccactac tactactacg gtatggacgt c 51 <210> 456 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 456 Ala Lys Asp Met Ser Gly Tyr Ala His Tyr Tyr Tyr Tyr Gly Met Asp 1 5 10 15 Val <210> 457 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 457 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag agttacagta cccctccgat caccttcggc 300 caagggacac gactggagat taaa 324 <210> 458 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 458 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 459 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 459 cagagcatta gcagctat 18 <210> 460 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 460 Gln Ser Ile Ser Ser Tyr 1 5 <210> 461 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 461 gctgcatcc 9 <210> 462 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 462 Ala Ala Ser One <210> 463 <211> 30 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 463 caacagagtt acagtacccc tccgatcacc 30 <210> 464 <211> 10 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 464 Gln Gln Ser Tyr Ser Thr Pro Pro Ile Thr 1 5 10 <210> 465 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 465 gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctccgat attagttgga atagtggtag cataggctat 180 gcggactctg tgaagggccg attcaccgtc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag aggtgaggac acggccctgt attactgtgc aaaagatatg 300 agtggctacg cccactacgg ctactacggt atggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 466 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 466 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Gly Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Met Ser Gly Tyr Ala His Tyr Gly Tyr Tyr Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 467 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 467 ggattcacct ttgatgatta tacc 24 <210> 468 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 468 Gly Phe Thr Phe Asp Asp Tyr Thr 1 5 <210> 469 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 469 attagttgga attagtggtag cata 24 <210> 470 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 470 Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <210> 471 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 471 gcaaaagata tgagtggcta cgcccactac ggctactacg gtatggacgt c 51 <210> 472 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 472 Ala Lys Asp Met Ser Gly Tyr Ala His Tyr Gly Tyr Tyr Gly Met Asp 1 5 10 15 Val <210> 473 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 473 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gagcattagg aactatttaa attggtatca gcagaaacca 120 gggaaagtcc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag agttacagta accctccgat caccttcggc 300 caagggacac gactggagat taaa 324 <210> 474 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 474 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Arg Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Asn Pro Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 475 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 475 cagagcatta ggaactat 18 <210> 476 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 476 Gln Ser Ile Arg Asn Tyr 1 5 <210> 477 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 477 gctgcatcc 9 <210> 478 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 478 Ala Ala Ser One <210> 479 <211> 30 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 479 caacagagtt acagtaaccc tccgatcacc 30 <210> 480 <211> 10 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 480 Gln Gln Ser Tyr Ser Asn Pro Pro Ile Thr 1 5 10 <210> 481 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 481 gaagcgcagc tggtggaatc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtacaa cctctggatt cacctttgat gattatacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg gatctctgat attagttgga atggtggaac caaaggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaaaaa ctccctgtat 240 ctgcaaatgg acagtctgag aggtgaggac acggccttat attactgtgt aaaagataaa 300 agtggctacg ggcacttcta cttcggtttg gacgtctggg gccaagggac cacggtcacc 360 gtctcctca 369 <210> 482 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 482 Glu Ala Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Thr Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Ser Asp Ile Ser Trp Asn Gly Gly Thr Lys Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asp Ser Leu Arg Gly Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Val Lys Asp Lys Ser Gly Tyr Gly His Phe Tyr Phe Gly Leu Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 483 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 483 ggattcacct ttgatgatta tacc 24 <210> 484 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 484 Gly Phe Thr Phe Asp Asp Tyr Thr 1 5 <210> 485 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 485 attagttgga atggtggaac caaa 24 <210> 486 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 486 Ile Ser Trp Asn Gly Gly Thr Lys 1 5 <210> 487 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 487 gtaaaagata aaagtggcta cgggcacttc tacttcggtt tggacgtc 48 <210> 488 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 488 Val Lys Asp Lys Ser Gly Tyr Gly His Phe Tyr Phe Gly Leu Asp Val 1 5 10 15 <210> 489 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 489 gacatccaga tgacccagtc tccatcctcc ctgactgcgt ctgtaggaga cagagtcacc 60 ttcacttgcc gggcaagtca gagcattagc aggcatttaa gttggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatgct gcatccagtt tggaaagtgg ggtcccttca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaccct 240 gaagattttg caacttacta ctgtcaacag agctacagta accctccgat caccttcggc 300 caagggacac gactggagat taaa 324 <210> 490 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 490 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Thr Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Phe Thr Cys Arg Ala Ser Gln Ser Ile Ser Arg His 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu His Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Asn Pro Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 491 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 491 cagagcatta gcaggcat 18 <210> 492 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 492 Gln Ser Ile Ser Arg His 1 5 <210> 493 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 493 gctgcatcc 9 <210> 494 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 494 Ala Ala Ser One <210> 495 <211> 30 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 495 caacagagct acagtaaccc tccgatcacc 30 <210> 496 <211> 10 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 496 Gln Gln Ser Tyr Ser Asn Pro Pro Ile Thr 1 5 10 <210> 497 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 497 gaagtgcagt tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt caagtttgct gattatgcca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcagag attagttgga atagtggtag cataggttat 180 gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgt aaaagataaa 300 agtggctacg ggcactacta tatcggtatg gacgtctggg gccaagggac cacggtcatc 360 gtctcctcc 369 <210> 498 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 498 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Ala Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Glu Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Val Lys Asp Lys Ser Gly Tyr Gly His Tyr Tyr Ile Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Ile Val Ser Ser 115 120 <210> 499 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 499 ggattcaagt ttgctgatta tgcc 24 <210> 500 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 500 Gly Phe Lys Phe Ala Asp Tyr Ala 1 5 <210> 501 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 501 attagttgga attagtggtag cata 24 <210> 502 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 502 Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <210> 503 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 503 gtaaaagata aaagtggcta cgggcactac tatatcggta tggacgtc 48 <210> 504 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 504 Val Lys Asp Lys Ser Gly Tyr Gly His Tyr Tyr Ile Gly Met Asp Val 1 5 10 15 <210> 505 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 505 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gagattagc agctatttaa attggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag agttacagta cccctccgat caccttcggc 300 caagggacac gactggagat taaa 324 <210> 506 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 506 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 507 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 507 cagagtatta gcagctat 18 <210> 508 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 508 Gln Ser Ile Ser Ser Tyr 1 5 <210> 509 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 509 gctgcatcc 9 <210> 510 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 510 Ala Ala Ser One <210> 511 <211> 30 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 511 caacagagtt acagtacccc tccgatcacc 30 <210> 512 <211> 10 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 512 Gln Gln Ser Tyr Ser Thr Pro Pro Ile Thr 1 5 10 <210> 513 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 513 gaagtgcacc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctccgat attagttgga atagtggtag cataggctat 180 gcggactctg tgaagggccg attcaccgtc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag aggtgaggac acggccttgt attactgtgc aaaagatatg 300 agtggctacg gccactacgg caagtacggt atggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 514 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 514 Glu Val His Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Gly Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Met Ser Gly Tyr Gly His Tyr Gly Lys Tyr Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 515 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 515 ggattcacct ttgatgatta tacc 24 <210> 516 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 516 Gly Phe Thr Phe Asp Asp Tyr Thr 1 5 <210> 517 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 517 attagttgga attagtggtag cata 24 <210> 518 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 518 Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <210> 519 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 519 gcaaaagata tgagtggcta cggccactac ggcaagtacg gtatggacgt c 51 <210> 520 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 520 Ala Lys Asp Met Ser Gly Tyr Gly His Tyr Gly Lys Tyr Gly Met Asp 1 5 10 15 Val <210> 521 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 521 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gagcattagg agctatttaa attggtatca gcagaaacca 120 gggaaagtcc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcaacag tctgcaacct 240 gacgattttg caacttacta ctgtcaacag acttacagta accctccgat caccttcggc 300 caagggacac gactggagat taaa 324 <210> 522 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 522 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Arg Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Tyr Ser Asn Pro Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 523 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 523 cagagcatta ggagctat 18 <210> 524 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 524 Gln Ser Ile Arg Ser Tyr 1 5 <210> 525 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 525 gctgcatcc 9 <210> 526 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 526 Ala Ala Ser One <210> 527 <211> 30 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 527 caacagactt acagtaaccc tccgatcacc 30 <210> 528 <211> 10 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 528 Gln Gln Thr Tyr Ser Asn Pro Pro Ile Thr 1 5 10 <210> 529 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 529 gaggtgcagc tggtggagtc tgggggagac ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaatt attagttgga atggtaatac cattgactat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 cttcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagataag 300 agtggctacg gacacttcta ctattacgtt ttggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 530 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 530 Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ile Ile Ser Trp Asn Gly Asn Thr Ile Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Lys Ser Gly Tyr Gly His Phe Tyr Tyr Tyr Val Leu Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 531 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 531 ggattcacct ttgatgatta tacc 24 <210> 532 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 532 Gly Phe Thr Phe Asp Asp Tyr Thr 1 5 <210> 533 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 533 attagttgga atggtaatac catt 24 <210> 534 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 534 Ile Ser Trp Asn Gly Asn Thr Ile 1 5 <210> 535 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 535 gcaaaagata agagtggcta cggacacttc tactattacg ttttggacgt c 51 <210> 536 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 536 Ala Lys Asp Lys Ser Gly Tyr Gly His Phe Tyr Tyr Tyr Val Leu Asp 1 5 10 15 Val <210> 537 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 537 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gagcattaac aactatttaa attggtatca gcagaaacca 120 gggaaagccc ctaaactcct gatctatgct gcttccagtt tgcaaagtgg ggtcccgtca 180 aggttcagtg gcagtggttc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctctcaacag agttacagtt tcccgtggac gttcggccaa 300 gggaccaagg tggaaatcaa a 321 <210> 538 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 538 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Ser Gln Gln Ser Tyr Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 539 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 539 cagagcatta acaactat 18 <210> 540 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 540 Gln Ser Ile Asn Asn Tyr 1 5 <210> 541 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 541 gctgcttcc 9 <210> 542 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 542 Ala Ala Ser One <210> 543 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 543 caacagagtt acagtttccc gtggacg 27 <210> 544 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 544 Gln Gln Ser Tyr Ser Phe Pro Trp Thr 1 5 <210> 545 <211> 363 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 545 caggtgcagc tggtggagtc ggggggaggc gtggtccagc ctgggaggtc cctgagaccc 60 tcctgtgcag cgtctggatt tagtttcagg gactatggca tgcactgggt ccgccaggct 120 ccaggtaagg gactagagtg gatggcacac atatggtata atggaaagaa taaatattat 180 gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctatat 240 ctgcaaatga acagcctgag acccgaggac acggctgtat attattgtgc gagagatggt 300 gtatcagcac gtggtactcc atttgactac tggggccagg gaaccctggt caccgtctcc 360 tca 363 <210> 546 <211> 121 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 546 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Pro Ser Cys Ala Ala Ser Gly Phe Ser Phe Arg Asp Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Ala His Ile Trp Tyr Asn Gly Lys Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Val Ser Ala Arg Gly Thr Pro Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 547 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 547 ggatttagtt tcagggacta tggc 24 <210> 548 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 548 Gly Phe Ser Phe Arg Asp Tyr Gly 1 5 <210> 549 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 549 atatggtata atggaaagaa taaa 24 <210> 550 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 550 Ile Trp Tyr Asn Gly Lys Asn Lys 1 5 <210> 551 <211> 42 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 551 gcgagagatg gtgtatcagc acgtggtact ccatttgact ac 42 <210> 552 <211> 14 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 552 Ala Arg Asp Gly Val Ser Ala Arg Gly Thr Pro Phe Asp Tyr 1 5 10 <210> 553 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 553 gaaacgacac tcacgcagtc tccagcattc atgtcagcgg ctccaggaga caaagtcagc 60 atctcctgca ttgccagcca gtacattgat gatgatgtga actggtacca acagaaacca 120 ggagaaactg ctattttcat tattcaagaa gcttctactc tcgttcctgg aatctcacct 180 cgattcagtg gcagcgggta tggaacacat tttaccctca caattaataa catagattct 240 gaggatgctg cattttactt ctgtctccaa catgataatt tcccgtacac ttttggccag 300 gggaccaagc tggagatcaa a 321 <210> 554 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 554 Glu Thr Thr Leu Thr Gln Ser Pro Ala Phe Met Ser Ala Ala Pro Gly 1 5 10 15 Asp Lys Val Ser Ile Ser Cys Ile Ala Ser Gln Tyr Ile Asp Asp Asp 20 25 30 Val Asn Trp Tyr Gln Gln Lys Pro Gly Glu Thr Ala Ile Phe Ile Ile 35 40 45 Gln Glu Ala Ser Thr Leu Val Pro Gly Ile Ser Pro Arg Phe Ser Gly 50 55 60 Ser Gly Tyr Gly Thr His Phe Thr Leu Thr Ile Asn Asn Ile Asp Ser 65 70 75 80 Glu Asp Ala Ala Phe Tyr Phe Cys Leu Gln His Asp Asn Phe Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 555 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 555 cagtacattg atgatgat 18 <210> 556 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 556 Gln Tyr Ile Asp Asp Asp 1 5 <210> 557 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 557 gaagcttct 9 <210> 558 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 558 Glu Ala Ser One <210> 559 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 559 ctccaacatg ataatttccc gtacact 27 <210> 560 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 560 Leu Gln His Asp Asn Phe Pro Tyr Thr 1 5 <210> 561 <211> 384 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 561 caggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctcttattt cacctttagc agttttgcca tgaactgggt ccgccaggct 120 ccagggcagg gcctggagtg ggtctcagct attagtggta gggtctcagc tattagtggt 180 agtggtggta tcacatacta cgcagactcc gtgaagggcc ggttcatcat ctccagagac 240 aattccaaga acacgctgta tctgcaaatg agcggcctga gagccgagga cacggccgta 300 tattactgtg cgaaaggccc ctatttgact acagtcaccc cctttgacta ctggggccag 360 ggaaccctgg tcaccgtctc ctca 384 <210> 562 <211> 128 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 562 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Tyr Phe Thr Phe Ser Ser Phe 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Arg Val Ser Ala Ile Ser Gly Ser Gly Gly Ile 50 55 60 Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp 65 70 75 80 Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Ser Gly Leu Arg Ala Glu 85 90 95 Asp Thr Ala Val Tyr Cys Ala Lys Gly Pro Tyr Leu Thr Thr Val 100 105 110 Thr Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 563 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 563 tatttcacct ttagcagttt tgcc 24 <210> 564 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 564 Tyr Phe Thr Phe Ser Ser Phe Ala 1 5 <210> 565 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 565 attagtggta gtggtggtat caca 24 <210> 566 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 566 Ile Ser Gly Ser Gly Gly Ile Thr 1 5 <210> 567 <211> 42 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 567 gcgaaaggcc cctatttgac tacagtcacc ccctttgact ac 42 <210> 568 <211> 14 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 568 Ala Lys Gly Pro Tyr Leu Thr Thr Val Thr Pro Phe Asp Tyr 1 5 10 <210> 569 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 569 gacatccagt tgacccagtc tccatcttcc gtgtctgcat ctgtcggaga cagagtcacc 60 atcacttgtc gggcgagtca ggggattagc agctggttag cctggtatca gcagaaacca 120 gggaaagccc ctaaactcct gatctatgct gtatccagtt tgcaaaatgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagat ttcaccctca ccatcagcag cctgcagcct 240 gaagactttg caacttacta ttgtcaacag gctaacagtt tcccattcac tttcggccct 300 gggaccaagc tggagatcaa acga 324 <210> 570 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 570 Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Val Ser Ser Leu Gln Asn Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 571 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 571 caggggatta gcagctgg 18 <210> 572 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 572 Gln Gly Ile Ser Ser Trp 1 5 <210> 573 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 573 gctgtatcc 9 <210> 574 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 574 Ala Val Ser One <210> 575 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 575 caacaggcta acagtttccc attcact 27 <210> 576 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 576 Gln Gln Ala Asn Ser Phe Pro Phe Thr 1 5 <210> 577 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 577 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgct gattatgcca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag tataggttat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggccttat attactgtgt aaaagataat 300 agtggctacg catcctacta ctacggtatg gacgtctggg gccaagggac cacggtcacc 360 gtctcctca 369 <210> 578 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 578 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Val Lys Asp Asn Ser Gly Tyr Ala Ser Tyr Tyr Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 579 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 579 ggattcacct ttgctgatta tgcc 24 <210> 580 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 580 Gly Phe Thr Phe Ala Asp Tyr Ala 1 5 <210> 581 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 581 attagttgga attagtggtag tata 24 <210> 582 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 582 Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <210> 583 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 583 gtaaaagata atagtggcta cgcatcctac tactacggta tggacgtc 48 <210> 584 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 584 Val Lys Asp Asn Ser Gly Tyr Ala Ser Tyr Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 585 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 585 gacatccagt tgacccagtc cccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180 aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag cctgcagcct 240 gaagatattg caacatatta ctgtcaacag tatgataatc tcccattcac tttcggccct 300 gggaccaaag tggatatcaa acga 324 <210> 586 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 586 Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105 <210> 587 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 587 cagagcatta gcagctat 18 <210> 588 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 588 Gln Ser Ile Ser Ser Tyr 1 5 <210> 589 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 589 gatgcatcc 9 <210> 590 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 590 Asp Ala Ser One <210> 591 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 591 caacagtatg ataatctccc attcact 27 <210> 592 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 592 Gln Gln Tyr Asp Asn Leu Pro Phe Thr 1 5 <210> 593 <211> 378 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 593 gaggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagt aactatggca tgcactgggt ccgccaggct 120 ccaggcaaag ggctggagtg ggtgacagtt atattacatg atggaagtta taaatactat 180 gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctacat 240 ctgcaaatga acagcctgag aactgaggac acggctgtat attactgtgc gaaagggcct 300 atgtttcggg gagtcccctta caaccactac tatggtatgg acgtctgggg ccaagggacc 360 acggtcaccg tctcctca 378 <210> 594 <211> 126 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 594 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Val Ile Leu His Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu His 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Pro Met Phe Arg Gly Val Pro Tyr Asn His Tyr Tyr Gly 100 105 110 Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 595 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 595 ggattcacct tcagtaacta tggc 24 <210> 596 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 596 Gly Phe Thr Phe Ser Asn Tyr Gly 1 5 <210> 597 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 597 atattacatg atggaagtta taaa 24 <210> 598 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 598 Ile Leu His Asp Gly Ser Tyr Lys 1 5 <210> 599 <211> 57 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 599 gcgaaagggc ctatgtttcg gggagtccct tacaaccact actatggtat ggacgtc 57 <210> 600 <211> 19 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 600 Ala Lys Gly Pro Met Phe Arg Gly Val Pro Tyr Asn His Tyr Tyr Gly 1 5 10 15 Met Asp Val <210> 601 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 601 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gggcatcaga aatgatttag gctggtatca gcagaaacca 120 gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtctcatca 180 aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240 gaagattttg caacttatta ctgtctacag cataatagtt acccgtacac ttttggccag 300 gggaccaagg tggaaatcaa acga 324 <210> 602 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 602 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Ser Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 603 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 603 cagggcatca gaaatgat 18 <210> 604 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 604 Gln Gly Ile Arg Asn Asp 1 5 <210> 605 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 605 gctgcatcc 9 <210> 606 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 606 Ala Ala Ser One <210> 607 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 607 ctacagcata atagttaccc gtacact 27 <210> 608 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 608 Leu Gln His Asn Ser Tyr Pro Tyr Thr 1 5 <210> 609 <211> 357 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 609 gaggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtacag cgtcaggttt ccccttcagt cgctatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggaatg ggtgacattt atatggtatg atggaagtaa taaatactat 180 gcagactccg cgaagggccg attcaccatc accagagaca attccaagaa cacggtgtat 240 ctgcaaatgg acagcctgag agccgatgac acggctgttt attattgtgt gagagatcag 300 gcagctctct actattttga ctcttggggc cagggaaccc tggtcaccgt ctcctca 357 <210> 610 <211> 119 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 610 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Pro Phe Ser Arg Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Phe Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Ala 50 55 60 Lys Gly Arg Phe Thr Ile Thr Arg Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asp Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Asp Gln Ala Ala Leu Tyr Tyr Phe Asp Ser Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 611 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 611 ggtttcccct tcagtcgcta tggc 24 <210> 612 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 612 Gly Phe Pro Phe Ser Arg Tyr Gly 1 5 <210> 613 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 613 atatggtatg atggaagtaa taaa 24 <210> 614 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 614 Ile Trp Tyr Asp Gly Ser Asn Lys 1 5 <210> 615 <211> 36 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 615 gtgagagatc aggcagctct ctactatttt gactct 36 <210> 616 <211> 12 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 616 Val Arg Asp Gln Ala Ala Leu Tyr Tyr Phe Asp Ser 1 5 10 <210> 617 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 617 gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc gggcgagtca gggtattagc aggtggttag cctggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctctgct gcatccagtt tgcaaagtgg agtcccatca 180 aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcgg cctgcagcct 240 gaagattttg caacttacta ttgtcaaaag gctaacagtt tccctttcac tttcggccct 300 gggaccaagc tggagatcaa acga 324 <210> 618 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 618 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Arg Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Ser Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Gly Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Lys Ala Asn Ser Phe Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 619 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 619 cagggtatta gcaggtgg 18 <210> 620 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 620 Gln Gly Ile Ser Arg Trp 1 5 <210> 621 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 621 gctgcatcc 9 <210> 622 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 622 Ala Ala Ser One <210> 623 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 623 caaaaggcta acagtttccc tttcact 27 <210> 624 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 624 Gln Lys Ala Asn Ser Phe Pro Phe Thr 1 5 <210> 625 <211> 378 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 625 gaggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagt agttatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtgacagtt atattacatg atggaagtaa tagatactct 180 gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctttat 240 ctgcaaatga acatcctgag agttgaggac acggctgtgt attactgtac gaaaggggct 300 atggttcggg gagtccctta caatcactac tacggcatgg acgtctgggg ccaagggacc 360 acggtcaccg tctcctca 378 <210> 626 <211> 126 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 626 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Val Ile Leu His Asp Gly Ser Asn Arg Tyr Ser Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ile Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Lys Gly Ala Met Val Arg Gly Val Pro Tyr Asn His Tyr Tyr Gly 100 105 110 Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 627 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 627 ggattcacct tcagtagtta tggc 24 <210> 628 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 628 Gly Phe Thr Phe Ser Ser Tyr Gly 1 5 <210> 629 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 629 atattacatg atggaagtaa taga 24 <210> 630 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 630 Ile Leu His Asp Gly Ser Asn Arg 1 5 <210> 631 <211> 57 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 631 acgaaagggg ctatggttcg gggagtccct tacaatcact actacggcat ggacgtc 57 <210> 632 <211> 19 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 632 Thr Lys Gly Ala Met Val Arg Gly Val Pro Tyr Asn His Tyr Tyr Gly 1 5 10 15 Met Asp Val <210> 633 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 633 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120 gggaaagccc ctaagcgcct aatctatgct gcatccattt tgcaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240 gaagattttg caacttatta ctgtctacag cataatagtt acccgtacac ttttggccag 300 gggaccaagc tggagatcaa acga 324 <210> 634 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 634 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Ile Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 635 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 635 cagggcatta gaaatgat 18 <210> 636 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 636 Gln Gly Ile Arg Asn Asp 1 5 <210> 637 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 637 gctgcatcc 9 <210> 638 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 638 Ala Ala Ser One <210> 639 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 639 ctacagcata atagttaccc gtacact 27 <210> 640 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 640 Leu Gln His Asn Ser Tyr Pro Tyr Thr 1 5 <210> 641 <211> 378 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 641 gaggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtgacagtt atattacatg atggaagtaa tagatactat 180 gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctttat 240 ctgcaaatga acatcctgag agctgaggac acggctgtgt attactgtac gaaaggggct 300 atggttcggg gagtccctta caatcactac tacggcatgg acgtctgggg ccaagggacc 360 acggtcaccg tctcctca 378 <210> 642 <211> 126 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 642 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Thr Val Ile Leu His Asp Gly Ser Asn Arg Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ile Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Lys Gly Ala Met Val Arg Gly Val Pro Tyr Asn His Tyr Tyr Gly 100 105 110 Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 643 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 643 ggattcacct tcagtagcta tggc 24 <210> 644 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 644 Gly Phe Thr Phe Ser Ser Tyr Gly 1 5 <210> 645 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 645 atattacatg atggaagtaa taga 24 <210> 646 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 646 Ile Leu His Asp Gly Ser Asn Arg 1 5 <210> 647 <211> 57 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 647 acgaaagggg ctatggttcg gggagtccct tacaatcact actacggcat ggacgtc 57 <210> 648 <211> 19 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 648 Thr Lys Gly Ala Met Val Arg Gly Val Pro Tyr Asn His Tyr Tyr Gly 1 5 10 15 Met Asp Val <210> 649 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 649 gacatcgtga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120 gggaaagccc ctaagcgcct gatctatgct gcatccaatt tgcaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240 gaagattttg caacttatta ctgtctacag cataatagtt acccgtacac ttttggccag 300 gggaccaagc tggagatcaa acga 324 <210> 650 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 650 Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 651 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 651 cagggcatta gaaatgat 18 <210> 652 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 652 Gln Gly Ile Arg Asn Asp 1 5 <210> 653 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 653 gctgcatcc 9 <210> 654 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 654 Ala Ala Ser One <210> 655 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 655 ctacagcata atagttaccc gtacact 27 <210> 656 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 656 Leu Gln His Asn Ser Tyr Pro Tyr Thr 1 5 <210> 657 <211> 378 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 657 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180 gcagactccg tgaagggccg attcaccatc tccagagact attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agctgaggac acggctgtgt tttactgtgc gaaaggggct 300 atggttcggg gagtccctta caactactac tacggtatgg acgtctgggg ccaagggacc 360 acggtcaccg tctcctca 378 <210> 658 <211> 126 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 658 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Tyr Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Phe Tyr Cys 85 90 95 Ala Lys Gly Ala Met Val Arg Gly Val Pro Tyr Asn Tyr Tyr Tyr Gly 100 105 110 Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 659 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 659 ggattcacct tcagtagcta tggc 24 <210> 660 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 660 Gly Phe Thr Phe Ser Ser Tyr Gly 1 5 <210> 661 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 661 atatcatatg atggaagtaa taaa 24 <210> 662 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 662 Ile Ser Tyr Asp Gly Ser Asn Lys 1 5 <210> 663 <211> 57 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 663 gcgaaagggg ctatggttcg gggagtccct tacaactact actacggtat ggacgtc 57 <210> 664 <211> 19 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 664 Ala Lys Gly Ala Met Val Arg Gly Val Pro Tyr Asn Tyr Tyr Tyr Gly 1 5 10 15 Met Asp Val <210> 665 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 665 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtttca gcagaaacca 120 gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240 gaagattttg caacttatta ctgtctacag cataatagtt acccgtacac ttttggccag 300 gggaccaagc tggagatcaa a 321 <210> 666 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 666 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 667 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 667 cagggcatta gaaatgat 18 <210> 668 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 668 Gln Gly Ile Arg Asn Asp 1 5 <210> 669 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 669 gctgcatcc 9 <210> 670 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 670 Ala Ala Ser One <210> 671 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 671 ctacagcata atagttaccc gtacact 27 <210> 672 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 672 Leu Gln His Asn Ser Tyr Pro Tyr Thr 1 5 <210> 673 <211> 378 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 673 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cctctggact caccttcagt agctatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180 acagactccg tgaagggccg attcaccatc tccagagaca attctaagaa cacgctgtat 240 ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaggggcc 300 atggttcggg gagtccctta caactactac tacggtatgg acgtctgggg ccaagggacc 360 acggtcaccg tctcctca 378 <210> 674 <211> 126 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 674 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Thr Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Ala Met Val Arg Gly Val Pro Tyr Asn Tyr Tyr Tyr Gly 100 105 110 Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 675 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 675 ggactcacct tcagtagcta tggc 24 <210> 676 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 676 Gly Leu Thr Phe Ser Ser Tyr Gly 1 5 <210> 677 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 677 atatcatatg atggaagtaa taaa 24 <210> 678 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 678 Ile Ser Tyr Asp Gly Ser Asn Lys 1 5 <210> 679 <211> 57 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 679 gcgaaagggg ccatggttcg gggagtccct tacaactact actacggtat ggacgtc 57 <210> 680 <211> 19 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 680 Ala Lys Gly Ala Met Val Arg Gly Val Pro Tyr Asn Tyr Tyr Tyr Gly 1 5 10 15 Met Asp Val <210> 681 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 681 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120 gggaaagccc ctaagcgcct gatctatgct gcgtccagtt tgcaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240 gaagattttg caacttatta ctgtctacag cataatagtt acccgtacac ttttggccag 300 gggaccaagc tggagatcaa a 321 <210> 682 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 682 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 683 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 683 cagggcatta gaaatgat 18 <210> 684 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 684 Gln Gly Ile Arg Asn Asp 1 5 <210> 685 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 685 gctgcgtcc 9 <210> 686 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 686 Ala Ala Ser One <210> 687 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 687 ctacagcata atagttaccc gtacact 27 <210> 688 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 688 Leu Gln His Asn Ser Tyr Pro Tyr Thr 1 5 <210> 689 <211> 378 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 689 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagg agctttggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtt atttcatatg atggaaatta taaatactat 180 gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agctgaggac acggctgtac attactgtgc gaaaggggct 300 atggttcggg gagtccctta caacttctac tacggtatgg acgtctgggg ccaagggacc 360 acggtcaccg tctcctca 378 <210> 690 <211> 126 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 690 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Asn Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val His Tyr Cys 85 90 95 Ala Lys Gly Ala Met Val Arg Gly Val Pro Tyr Asn Phe Tyr Tyr Gly 100 105 110 Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 691 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 691 ggattcacct tcaggagctt tggc 24 <210> 692 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 692 Gly Phe Thr Phe Arg Ser Phe Gly 1 5 <210> 693 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 693 atttcatatg atggaaatta taaa 24 <210> 694 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 694 Ile Ser Tyr Asp Gly Asn Tyr Lys 1 5 <210> 695 <211> 57 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 695 gcgaaagggg ctatggttcg gggagtccct tacaacttct actacggtat ggacgtc 57 <210> 696 <211> 19 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 696 Ala Lys Gly Ala Met Val Arg Gly Val Pro Tyr Asn Phe Tyr Tyr Gly 1 5 10 15 Met Asp Val <210> 697 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 697 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca ggtcattaga aatgatttag gctggtatca gcagaaacca 120 gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg gatcccatca 180 aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240 gaagattttg caacttatta ctgtctacag cataatagtt acccgtacac ttttggccag 300 gggaccaagc tggagatcaa a 321 <210> 698 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 698 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Val Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 699 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 699 caggtcatta gaaatgat 18 <210> 700 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 700 Gln Val Ile Arg Asn Asp 1 5 <210> 701 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 701 gctgcatcc 9 <210> 702 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 702 Ala Ala Ser One <210> 703 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 703 ctacagcata atagttaccc gtacact 27 <210> 704 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 704 Leu Gln His Asn Ser Tyr Pro Tyr Thr 1 5 <210> 705 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 705 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatacca tgcactgggt ccggcaagtt 120 ccaggaaagg gcctggagtg gatctcaggt attagttgga atagtggtag catggactat 180 gcggactctg tgaagggccg attcaccatc tctagagaca acgccaggaa ctccctgttt 240 ctgcaaatga acagtgtgag aactgaggac acggccttgt attactgtgc aaaagataag 300 agtggctacg gctccttcta ctacggtatg gacgtctggg gccaggggac cacggtcacc 360 gtctcctca 369 <210> 706 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 706 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Met Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ser Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Val Arg Thr Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Lys Ser Gly Tyr Gly Ser Phe Tyr Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 707 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 707 ggattcacct ttgatgatta tacc 24 <210> 708 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 708 Gly Phe Thr Phe Asp Asp Tyr Thr 1 5 <210> 709 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 709 attagttgga atagtggtag catg 24 <210> 710 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 710 Ile Ser Trp Asn Ser Gly Ser Met 1 5 <210> 711 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 711 gcaaaagata agagtggcta cggctccttc tactacggta tggacgtc 48 <210> 712 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 712 Ala Lys Asp Lys Ser Gly Tyr Gly Ser Phe Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 713 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 713 gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga cagagccacc 60 ctctcctgca gggccagtca gagtgtcagc agcatctact tagcctggta ccagcagaaa 120 cctggccagg ctcccaggct cctcatccat ggtgcgtcca ccagggccac tggcatccca 180 gacaggttca gtggcagtgg gtcagggaca gacttcactc tcaccatcag cagactggag 240 cctgaagatt ttgcagttta ttactgtcag cagcgtgctc actcaccgta cacttttggc 300 caggggacca agctggagat caaa 324 <210> 714 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 714 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Asp Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ile 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile His Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ala His Ser Pro 85 90 95 Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 715 <211> 21 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 715 cagagtgtca gcagcatcta c 21 <210> 716 <211> 7 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 716 Gln Ser Val Ser Ser Ile Tyr 1 5 <210> 717 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 717 ggtgcgtcc 9 <210> 718 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 718 Gly Ala Ser One <210> 719 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 719 cagcagcgtg ctcactcacc gtacact 27 <210> 720 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 720 Gln Gln Arg Ala His Ser Pro Tyr Thr 1 5 <210> 721 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 721 gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggctt cagctttgat aattatgcca tgcactgggt ccggcaagct 120 ccaggacagg gcctggagtg ggtctcaggt attagttgga atagtggtag cagagactat 180 gcggactctg tgaagggccg attcaccatc tccagagaca atgccaggaa ctccctgttt 240 ctgcaaatga acagtctgag taatgaggac acggccatgt attactgcgc aaaagataag 300 agtggctacg gctcctactt ctacggtatg gacgtctggg gccaagggac cacggtcacc 360 gtctcctca 369 <210> 722 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 722 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Asp Asn Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Arg Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ser Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Ser Asn Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Lys Asp Lys Ser Gly Tyr Gly Ser Tyr Phe Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 723 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 723 ggcttcagct ttgataatta tgcc 24 <210> 724 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 724 Gly Phe Ser Phe Asp Asn Tyr Ala 1 5 <210> 725 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 725 attagttgga attagtggtag caga 24 <210> 726 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 726 Ile Ser Trp Asn Ser Gly Ser Arg 1 5 <210> 727 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 727 gcaaaagata agagtggcta cggctcctac ttctacggta tggacgtc 48 <210> 728 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 728 Ala Lys Asp Lys Ser Gly Tyr Gly Ser Tyr Phe Tyr Gly Met Asp Val 1 5 10 15 <210> 729 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 729 gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga cagagccacc 60 ctctcctgca gggccagtca gagtattaga aacatctatt tagcctggta ccagcagaaa 120 cctggccagg ctcccaggct cctcatccat ggtgcgtcca ccagggccac tggcatccca 180 gacaggttca gtggcagtgg gtcagggaca gacttcactc tcaccatcag cagactggag 240 cctgaagatt ttgcagttta ttactgtcag cagcgtgtta gtttaccgta cacttttggc 300 caggggacca agctggagat caaa 324 <210> 730 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 730 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Asp Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Arg Asn Ile 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile His Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Val Ser Leu Pro 85 90 95 Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 731 <211> 21 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 731 cagagtatta gaaacatcta t 21 <210> 732 <211> 7 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 732 Gln Ser Ile Arg Asn Ile Tyr 1 5 <210> 733 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 733 ggtgcgtcc 9 <210> 734 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 734 Gly Ala Ser One <210> 735 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 735 cagcagcgtg ttagtttacc gtacact 27 <210> 736 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 736 Gln Gln Arg Val Ser Leu Pro Tyr Thr 1 5 <210> 737 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 737 caggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggctt cagctttgat gattatgcca tgcactgggt ccggcaagct 120 ccaggacagg gcctggagtg ggtctcaggt attagttgga atggtggtag cagagactat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaggaa ctccctgttt 240 ctgcaaatga acagtctgtt tactgaggac acggccttgt attactgtgc aaaagataag 300 agtggctacg gctcctactt ctacggtatg gacgtctggg gccaagggac cacggtcacc 360 gtctcctca 369 <210> 738 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 738 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Gly Gly Ser Arg Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ser Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Phe Thr Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Lys Ser Gly Tyr Gly Ser Tyr Phe Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 739 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 739 ggcttcagct ttgatgatta tgcc 24 <210> 740 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 740 Gly Phe Ser Phe Asp Asp Tyr Ala 1 5 <210> 741 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 741 attagttgga atggtggtag caga 24 <210> 742 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 742 Ile Ser Trp Asn Gly Gly Ser Arg 1 5 <210> 743 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 743 gcaaaagata agagtggcta cggctcctac ttctacggta tggacgtc 48 <210> 744 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 744 Ala Lys Asp Lys Ser Gly Tyr Gly Ser Tyr Phe Tyr Gly Met Asp Val 1 5 10 15 <210> 745 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 745 gaaattgtgt tgacgcagtc tccaggcatt ctgtctttgt ctccagggga cagagccacc 60 ctctcctgca gggccagtca gagtattaga aacatctatt tagcctggta ccagcagaaa 120 cctggccagg ctcccaggct cctcatccat ggtgcgtcca ccagggccac tggcatccca 180 gacaggttca gtggcagtgg gtcagggaca gacttcactc tcaccatcag cagactggag 240 cctgaagatt ttgcagttta ttactgtcag cagcgtgtta gttcaccgta cacttttggc 300 caggggacca agctggagat caaa 324 <210> 746 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 746 Glu Ile Val Leu Thr Gln Ser Pro Gly Ile Leu Ser Leu Ser Pro Gly 1 5 10 15 Asp Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Arg Asn Ile 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile His Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Val Ser Ser Pro 85 90 95 Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 747 <211> 21 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 747 cagagtatta gaaacatcta t 21 <210> 748 <211> 7 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 748 Gln Ser Ile Arg Asn Ile Tyr 1 5 <210> 749 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 749 ggtgcgtcc 9 <210> 750 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 750 Gly Ala Ser One <210> 751 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 751 cagcagcgtg ttagttcacc gtacact 27 <210> 752 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 752 Gln Gln Arg Val Ser Ser Pro Tyr Thr 1 5 <210> 753 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 753 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120 ccaggaaagg gcctggagtg ggtctcaggt attagttgga atagtggtag cagagactat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaggaa ctccctgttt 240 ctgcaaatga acagtctgag tactgaggac acggccttgt attactgtgc aaaagataag 300 agtggctacg gctcctacta ctacggtatg gacgtctggg gccaagggac cacggtcacc 360 gtctcctca 369 <210> 754 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 754 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Arg Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ser Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Ser Thr Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Lys Ser Gly Tyr Gly Ser Tyr Tyr Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 755 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 755 ggattcacct ttgatgatta tgcc 24 <210> 756 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 756 Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <210> 757 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 757 attagttgga attagtggtag caga 24 <210> 758 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 758 Ile Ser Trp Asn Ser Gly Ser Arg 1 5 <210> 759 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 759 gcaaaagata agagtggcta cggctcctac tactacggta tggacgtc 48 <210> 760 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 760 Ala Lys Asp Lys Ser Gly Tyr Gly Ser Tyr Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 761 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 761 gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga cagagccacc 60 ctctcctgca gggccagtca gagtattaga agcatctact tagcctggta ccagcagaaa 120 cctggccagg ctcccaggct cctcatccat ggtgcgtcca ccagggccac tggcatccca 180 gacaggttca gtggcagtgg gtcagggaca gacttcactc tcaccatcag cagactggag 240 cctgaagatt ttgcagttta ttactgtcag cagcgtgtta gctcaccgta cacttttggc 300 caggggacca agctggagat caaa 324 <210> 762 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 762 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Asp Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Arg Ser Ile 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile His Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Val Ser Ser Pro 85 90 95 Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 763 <211> 21 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 763 cagagtatta gaagcatcta c 21 <210> 764 <211> 7 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 764 Gln Ser Ile Arg Ser Ile Tyr 1 5 <210> 765 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 765 ggtgcgtcc 9 <210> 766 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 766 Gly Ala Ser One <210> 767 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 767 cagcagcgtg ttagctcacc gtacact 27 <210> 768 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 768 Gln Gln Arg Val Ser Ser Pro Tyr Thr 1 5 <210> 769 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 769 gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgtag cctctggatt cacctttgct gattttacca tgcactgggt ccggcaagcg 120 ccagggaagg gccttgagtg ggtctcaggt attagttgga atagtaatag tatagactat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa atccctgttt 240 ctgcaaatgt ccagtctgag agctgaggac acggccttat attactgtgt caaagacaga 300 agcggatata gcagattcta ctacggtatg gacgtctggg gccaagggac cacggtcacc 360 gtctcctca 369 <210> 770 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 770 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ala Asp Phe 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Asn Ser Ile Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Phe 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Val Lys Asp Arg Ser Gly Tyr Ser Arg Phe Tyr Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 771 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 771 ggattcacct ttgctgattt tacc 24 <210> 772 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 772 Gly Phe Thr Phe Ala Asp Phe Thr 1 5 <210> 773 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 773 attagttgga atagtaatag tata 24 <210> 774 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 774 Ile Ser Trp Asn Ser Asn Ser Ile 1 5 <210> 775 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 775 gtcaaagaca gaagcggata tagcagattc tactacggta tggacgtc 48 <210> 776 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 776 Val Lys Asp Arg Ser Gly Tyr Ser Arg Phe Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 777 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 777 gaaattgtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccatc 60 ctctcctgca gggccagtca gaatattaat agcaacttgg cctggtacca gcagaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tgtcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatccgcag cctgcaatct 240 gaagattttg cagtttatta ctgtcaacaa tattataatt ggccgatcac tttcggccac 300 gggacacgac tggagattaa a 321 <210> 778 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 778 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Ile Leu Ser Cys Arg Ala Ser Gln Asn Ile Asn Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Arg Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Asn Trp Pro Ile 85 90 95 Thr Phe Gly His Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 779 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 779 cagaatatta atagcaac 18 <210> 780 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 780 Gln Asn Ile Asn Ser Asn 1 5 <210> 781 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 781 ggtgcatcc 9 <210> 782 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 782 Gly Ala Ser One <210> 783 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 783 caacaatatt ataattggcc gatcact 27 <210> 784 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 784 Gln Gln Tyr Tyr Asn Trp Pro Ile Thr 1 5 <210> 785 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 785 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120 ccaggaaagg gcctggagtg ggtctcaggt attagttgga atggtggtag taaagactat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acaccaggaa ctccctgtct 240 ctgcaaatga acagtctgag aattgaagac acggccttat attactgtgc aaaagataag 300 agtggctacg gctccttcta ctacggtttg gacgtctggg gccaagggac cacggtcacc 360 gtctcctca 369 <210> 786 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 786 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Gly Gly Ser Lys Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Arg Asn Ser Leu Ser 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ile Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Lys Ser Gly Tyr Gly Ser Phe Tyr Tyr Gly Leu Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 787 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 787 ggattcacct ttgatgatta tgcc 24 <210> 788 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 788 Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <210> 789 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 789 attagttgga atggtggtag taaa 24 <210> 790 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 790 Ile Ser Trp Asn Gly Gly Ser Lys 1 5 <210> 791 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 791 gcaaaagata agagtggcta cggctccttc tactacggtt tggacgtc 48 <210> 792 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 792 Ala Lys Asp Lys Ser Gly Tyr Gly Ser Phe Tyr Tyr Gly Leu Asp Val 1 5 10 15 <210> 793 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 793 gaaatagtgt tgacacagtc tccaggcacc ctgtctttgt ctccagggga cagagccacc 60 ctctcctgca gggccagtca gagtattaga agcatctact tagcctggta ccagcagaaa 120 cctggccagg ctcccaggct cctcatccat ggtgcgtcca ccagggccac tggcatccca 180 gacaggttca gtggcagtgg gtcagggaca gacttcactc tcaccatcag cagactggag 240 cctgaagatt ttgcagttta ttactgtcag cagcgtgtta gctcaccgta cacttttggc 300 caggggacca agctggagat caaa 324 <210> 794 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 794 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Asp Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Arg Ser Ile 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile His Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Val Ser Ser Pro 85 90 95 Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 795 <211> 21 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 795 cagagtatta gaagcatcta c 21 <210> 796 <211> 7 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 796 Gln Ser Ile Arg Ser Ile Tyr 1 5 <210> 797 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 797 ggtgcgtcc 9 <210> 798 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 798 Gly Ala Ser One <210> 799 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 799 cagcagcgtg ttagctcacc gtacact 27 <210> 800 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 800 Gln Gln Arg Val Ser Ser Pro Tyr Thr 1 5 <210> 801 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 801 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gatttcacca tgcactgggt ccggcaagct 120 ccaggaaagg gcctggagtg ggtctcagat attagttgga atagtggtag catagactat 180 gcggactctg tgaagggccg attcaccatt tccagagaca atgccaggaa ctccctgttt 240 ctacaaatga gcagtctgag aactgaggac acggcctcgt attactgtat aaaagataag 300 agtggctacg gctcctacaa ctacggtctg gacgtctggg gccaagggac cacggtcacc 360 gtctcctca 369 <210> 802 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 802 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Phe 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Asn Ser Gly Ser Ile Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ser Leu Phe 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Thr Glu Asp Thr Ala Ser Tyr Tyr Cys 85 90 95 Ile Lys Asp Lys Ser Gly Tyr Gly Ser Tyr Asn Tyr Gly Leu Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 803 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 803 ggattcacct ttgatgattt cacc 24 <210> 804 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 804 Gly Phe Thr Phe Asp Asp Phe Thr 1 5 <210> 805 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 805 attagttgga attagtggtag cata 24 <210> 806 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 806 Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <210> 807 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 807 ataaaagata agagtggcta cggctcctac aactacggtc tggacgtc 48 <210> 808 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 808 Ile Lys Asp Lys Ser Gly Tyr Gly Ser Tyr Asn Tyr Gly Leu Asp Val 1 5 10 15 <210> 809 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 809 gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga cagagccacc 60 ctctcctgca gggccagtca gagtgttagc agcatctact tagcctggta ccagcagaaa 120 cctggccagg ctcccaggct cctcatccat ggtgcgtcca ccagggccac tggcatccca 180 gacaggttca gtggcagtgg gtcggggaca gacttcactc tcaccatcag cagactggag 240 cctgaagatt ttgcacttta ttactgtcac cagcgtgtta gttcaccgta cacttttggc 300 caggggacca agctggagat caaa 324 <210> 810 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 810 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Asp Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ile 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile His Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Leu Tyr Tyr Cys His Gln Arg Val Ser Ser Pro 85 90 95 Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 811 <211> 21 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 811 cagagtgtta gcagcatcta c 21 <210> 812 <211> 7 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 812 Gln Ser Val Ser Ser Ile Tyr 1 5 <210> 813 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 813 ggtgcgtcc 9 <210> 814 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 814 Gly Ala Ser One <210> 815 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 815 caccagcgtg ttagttcacc gtacact 27 <210> 816 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 816 His Gln Arg Val Ser Ser Pro Tyr Thr 1 5 <210> 817 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 817 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120 ccaggaaagg gcctggagtg ggtctcaggt attagttgga atagtggtag taaagactat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acaccaggaa ctccctgttt 240 ctgcaaatga acagtctgag aactgaagac acggccttat attactgtgc aaaagataag 300 agtggctacg gctccttcta ctacggtatg gacgtctggg gccaagggac cacggtcacc 360 gtctcctca 369 <210> 818 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 818 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Lys Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Arg Asn Ser Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Lys Ser Gly Tyr Gly Ser Phe Tyr Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 819 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 819 ggattcacct ttgatgatta tgcc 24 <210> 820 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 820 Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <210> 821 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 821 attagttgga attagtggtag taaa 24 <210> 822 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 822 Ile Ser Trp Asn Ser Gly Ser Lys 1 5 <210> 823 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 823 gcaaaagata agagtggcta cggctccttc tactacggta tggacgtc 48 <210> 824 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 824 Ala Lys Asp Lys Ser Gly Tyr Gly Ser Phe Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 825 <211> 318 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 825 gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggccagtca gagtattagt agctggttgg cctggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctataag gcgtctagtt tagaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240 gatgattttg caacttatta ctgccaacag tataatagtt attctccgtt cggccaaggg 300 accaaggtgg aaatcaaa 318 <210> 826 <211> 106 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 826 Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Pro 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 827 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 827 cagagtatta gtagctgg 18 <210> 828 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 828 Gln Ser Ile Ser Ser Trp 1 5 <210> 829 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 829 aaggcgtct 9 <210> 830 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 830 Lys Ala Ser One <210> 831 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 831 caacagtata atagttatc tccg 24 <210> 832 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 832 Gln Gln Tyr Asn Ser Tyr Ser Pro 1 5 <210> 833 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 833 caggtgcaac tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cctctggact caccttcagt acctatgtca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggcgtg ggtggcagtt atagcaaatg atggaagtaa taaatattat 180 gcagactccg tgaagggccg attcaccatc tccagagaca actccaagaa cacgctgtat 240 ctgcaaatga atagcctgag acctgaggac acggctgtgt atttttgtgc gaaagagggg 300 ggtaccagtg ggtcctacta ttactatgga atggacgtct ggggtcaagg gactacggtc 360 accgtctcct ca 372 <210> 834 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 834 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Ser Thr Tyr 20 25 30 Val Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Ala Trp Val 35 40 45 Ala Val Ile Ala Asn Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Lys Glu Gly Gly Thr Ser Gly Ser Tyr Tyr Tyr Tyr Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 835 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 835 ggactcacct tcagtaccta tgtc 24 <210> 836 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 836 Gly Leu Thr Phe Ser Thr Tyr Val 1 5 <210> 837 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 837 atagcaaatg atggaagtaa taaa 24 <210> 838 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 838 Ile Ala Asn Asp Gly Ser Asn Lys 1 5 <210> 839 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 839 gcgaaagagg ggggtaccag tgggtcctac tattactatg gaatggacgt c 51 <210> 840 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 840 Ala Lys Glu Gly Gly Thr Ser Gly Ser Tyr Tyr Tyr Tyr Gly Met Asp 1 5 10 15 Val <210> 841 <211> 342 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 841 gacatccaga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60 atcaactgca agtccagcca gagtctttta ttcaactcca tcaataagaa ctacttagct 120 tggtaccagc agaaaccagg acagcctcct aagcttctcc tttactgggc atctacccgg 180 gaatccggga tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240 atcaccagcc tgcaggctga agatgtggca ctttattact gtcagcaata ttatagtatt 300 ccgtggacgt tcggccaagg gaccaaggtg gaaatcaaac ga 342 <210> 842 <211> 114 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 842 Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Phe Asn 20 25 30 Ser Ile Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Leu Tyr Trp Ala Ser Thr Arg Glu Ser Gly Ile 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Thr Ser Leu Gln Ala Glu Asp Val Ala Leu Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Ser Ile Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg <210> 843 <211> 36 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 843 cagagtcttt tattcaactc catcaataag aactac 36 <210> 844 <211> 12 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 844 Gln Ser Leu Leu Phe Asn Ser Ile Asn Lys Asn Tyr 1 5 10 <210> 845 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 845 tgggcatct 9 <210> 846 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 846 Trp Ala Ser One <210> 847 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 847 cagcaatatt atagtattcc gtggacg 27 <210> 848 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 848 Gln Gln Tyr Tyr Ser Ile Pro Trp Thr 1 5 <210> 849 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 849 caggtgcagc tggtggagtc tggggctgaa gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaaga cttctggata caccttcacc ggctactata tgcactggat acgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcaacccta aaagtggtgg cacaaattat 180 gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240 atggaactga gcaggctgag atccgacgac atggccgtgt attattgtgc gagaatgggg 300 gacggtgcag tgtttgactt ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 850 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 850 Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr Met His Trp Ile Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Lys Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Met Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Met Gly Asp Gly Ala Val Phe Asp Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 851 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 851 ggatacacct tcaccggcta ctat 24 <210> 852 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 852 Gly Tyr Thr Phe Thr Gly Tyr Tyr 1 5 <210> 853 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 853 atcaacccta aaagtggtgg caca 24 <210> 854 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 854 Ile Asn Pro Lys Ser Gly Gly Thr 1 5 <210> 855 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 855 gcgagaatgg gggacggtgc agtgtttgac ttc 33 <210> 856 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 856 Ala Arg Met Gly Asp Gly Ala Val Phe Asp Phe 1 5 10 <210> 857 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 857 gccatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gaggattagc agctttttaa attggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatact gcatccaatt tacaaaatgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ctatcagcag tctgcaacct 240 gaagattttg ctacttacta ctgtcaacag agttacagga ccccgctcac tttcggcgga 300 gggaccaagg tggaaatcaa acga 324 <210> 858 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 858 Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Arg Ile Ser Ser Phe 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Thr Ala Ser Asn Leu Gln Asn Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Arg Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 859 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 859 cagaggatta gcagcttt 18 <210> 860 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 860 Gln Arg Ile Ser Ser Phe 1 5 <210> 861 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 861 actgcatcc 9 <210> 862 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 862 Thr Ala Ser One <210> 863 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 863 caacagagtt acaggacccc gctcact 27 <210> 864 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 864 Gln Gln Ser Tyr Arg Thr Pro Leu Thr 1 5 <210> 865 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 865 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga acagtggtag cataggctat 180 gcggactctg tgaagggccg attcaccatt tccagagaca acgccaagaa ctccctgtat 240 ttgcaaatga acagtctgag agctgaggac acggccttgt tttactgtgc aaaagatcaa 300 agtggttacg gccactacta ctacggtatg gacgtctggg gccaagggac cacggtcacc 360 gtctcctca 369 <210> 866 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 866 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Phe Tyr Cys 85 90 95 Ala Lys Asp Gln Ser Gly Tyr Gly His Tyr Tyr Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 867 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 867 ggattcacct ttgatgatta tacc 24 <210> 868 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 868 Gly Phe Thr Phe Asp Asp Tyr Thr 1 5 <210> 869 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 869 attagttgga acagtggtag cata 24 <210> 870 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 870 Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <210> 871 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 871 gcaaaagatc aaagtggtta cggccactac tactacggta tggacgtc 48 <210> 872 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 872 Ala Lys Asp Gln Ser Gly Tyr Gly His Tyr Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 873 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 873 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgta gggccagtca gagtgttagc agcaacttag cctggtacca gcagaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactga tatcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240 gaagattttg cagtttatca ctgtcagcag tataataact ggccgctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 874 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 874 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Asp Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr His Cys Gln Gln Tyr Asn Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 875 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 875 cagagtgtta gcagcaac 18 <210> 876 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 876 Gln Ser Val Ser Ser Asn 1 5 <210> 877 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 877 ggtgcatcc 9 <210> 878 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 878 Gly Ala Ser One <210> 879 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 879 cagcagtata ataactggcc gctcact 27 <210> 880 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 880 Gln Gln Tyr Asn Asn Trp Pro Leu Thr 1 5 <210> 881 <211> 387 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 881 gaggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagt tactatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtt atatcatttg atggaaagaa taaatattat 180 gcagactccg tgatgggccg attcaccatc tccagagaca attccaagaa tacactgtat 240 ctgcaaatga acagcctgag agctgaggac tcggctgtgt ttttctgtgc gaggtcttac 300 gacattttga ctggttatgg agccggttac agctaccact acggtatgga cgtctggggc 360 caagggacca cggtcaccgt ctcctca 387 <210> 882 <211> 129 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 882 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Phe Asp Gly Lys Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Met Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ser Ala Val Phe Phe Cys 85 90 95 Ala Arg Ser Tyr Asp Ile Leu Thr Gly Tyr Gly Ala Gly Tyr Ser Tyr 100 105 110 His Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser 115 120 125 Ser <210> 883 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 883 ggattcacct tcagttacta tggc 24 <210> 884 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 884 Gly Phe Thr Phe Ser Tyr Tyr Gly 1 5 <210> 885 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 885 atatcatttg atggaaagaa taaa 24 <210> 886 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 886 Ile Ser Phe Asp Gly Lys Asn Lys 1 5 <210> 887 <211> 66 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 887 gcgaggtctt acgacatttt gactggttat ggagccggtt acagctacca ctacggtatg 60 gacgtc 66 <210> 888 <211> 22 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 888 Ala Arg Ser Tyr Asp Ile Leu Thr Gly Tyr Gly Ala Gly Tyr Ser Tyr 1 5 10 15 His Tyr Gly Met Asp Val 20 <210> 889 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 889 gccatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gaggattagc agctttttaa attggtatca gcagaaacca 120 gggaaagccc ctaagctcct aatctatact gcatccaatt tacaaaatgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag agttacagga ccccgctcac tttcggcgga 300 gggaccaagg tggagatcaa acga 324 <210> 890 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 890 Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Arg Ile Ser Ser Phe 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Thr Ala Ser Asn Leu Gln Asn Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Arg Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 891 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 891 cagaggatta gcagcttt 18 <210> 892 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 892 Gln Arg Ile Ser Ser Phe 1 5 <210> 893 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 893 actgcatcc 9 <210> 894 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 894 Thr Ala Ser One <210> 895 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 895 caacagagtt acaggacccc gctcact 27 <210> 896 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 896 Gln Gln Ser Tyr Arg Thr Pro Leu Thr 1 5 <210> 897 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 897 caggtgcagc tggtggagtc tggggctgaa gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaaga cttctggata caccctctcc ggctattata tgcactggat gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg attaacccta aaagtggtgt cacaaattat 180 gcacagaagt ttcaggacag agtcgccatg accagggaca cgtccatcag cacagcctac 240 atggaactga gcaggctgag atctgacgac acggccgtgt attactgtgc gagaatgggg 300 gacggtgcag tgtttgactt ctgggcccag ggaaccctgg tcaccgtctc ctca 354 <210> 898 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 898 Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Leu Ser Gly Tyr 20 25 30 Tyr Met His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Lys Ser Gly Val Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Asp Arg Val Ala Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Met Gly Asp Gly Ala Val Phe Asp Phe Trp Ala Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 899 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 899 ggataccaccc tctccggcta ttat 24 <210> 900 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 900 Gly Tyr Thr Leu Ser Gly Tyr Tyr 1 5 <210> 901 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 901 attaacccta aaagtggtgt caca 24 <210> 902 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 902 Ile Asn Pro Lys Ser Gly Val Thr 1 5 <210> 903 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 903 gcgagaatgg gggacggtgc agtgtttgac ttc 33 <210> 904 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 904 Ala Arg Met Gly Asp Gly Ala Val Phe Asp Phe 1 5 10 <210> 905 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 905 gacatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gaggattagc agctttttaa attggtatca gcagaaacca 120 gggaaagccc ctaagctcct aatctatact gcatccaatt tacaaaatgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag agttacagga ccccgctcac tttcggcgga 300 gggaccaagc tggagatcaa acga 324 <210> 906 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 906 Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Arg Ile Ser Ser Phe 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Thr Ala Ser Asn Leu Gln Asn Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Arg Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 907 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 907 cagaggatta gcagcttt 18 <210> 908 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 908 Gln Arg Ile Ser Ser Phe 1 5 <210> 909 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 909 actgcatcc 9 <210> 910 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 910 Thr Ala Ser One <210> 911 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 911 caacagagtt acaggacccc gctcact 27 <210> 912 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 912 Gln Gln Ser Tyr Arg Thr Pro Leu Thr 1 5 <210> 913 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 913 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtgtcaact atatcatttg atggaagtaa caaatactat 180 gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag acctgaggac acggctgtgt attactgtgc gaaagggggg 300 ggtaccagtg ggtcctactt ttactacggt atggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 914 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 914 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Gly Gly Thr Ser Gly Ser Tyr Phe Tyr Tyr Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 915 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 915 ggattcacct tcagtagcta tggc 24 <210> 916 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 916 Gly Phe Thr Phe Ser Ser Tyr Gly 1 5 <210> 917 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 917 atatcatttg atggaagtaa caaa 24 <210> 918 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 918 Ile Ser Phe Asp Gly Ser Asn Lys 1 5 <210> 919 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 919 gcgaaagggg ggggtaccag tgggtcctac ttttactacg gtatggacgt c 51 <210> 920 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 920 Ala Lys Gly Gly Gly Thr Ser Gly Ser Tyr Phe Tyr Tyr Gly Met Asp 1 5 10 15 Val <210> 921 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 921 gccatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gaggattagc agctttttaa attggtatca gcagaaacca 120 gggaaagccc ctaagctcct aatctatact gcatccaatt tacaaaatgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag agttacagga ccccgctcac tttcggcgga 300 gggaccaagc tggagatcaa acga 324 <210> 922 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 922 Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Arg Ile Ser Ser Phe 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Thr Ala Ser Asn Leu Gln Asn Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Arg Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 923 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 923 cagaggatta gcagcttt 18 <210> 924 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 924 Gln Arg Ile Ser Ser Phe 1 5 <210> 925 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 925 actgcatcc 9 <210> 926 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 926 Thr Ala Ser One <210> 927 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 927 caacagagtt acaggacccc gctcact 27 <210> 928 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 928 Gln Gln Ser Tyr Arg Thr Pro Leu Thr 1 5 <210> 929 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 929 caggttcagc tggtgcagtc tgggactgag gtgaagaagc ctggggcctc aatgaaggtc 60 tcctgcaagg cttctggata caccttcacc ggctactata ttcactgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtgatgt cacaaagtat 180 gcacagaagt ttcagggcag ggtcaccttg accagggaca cgtccatcag tgcagcctat 240 attgacctga gcaggctgag atctgacgac acggccattt attactgtgc gagaatgggg 300 gacggtgcag tgtttgacta ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 930 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 930 Gln Val Gln Leu Val Gln Ser Gly Thr Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Met Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Asn Ser Asp Val Thr Lys Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Leu Thr Arg Asp Thr Ser Ile Ser Ala Ala Tyr 65 70 75 80 Ile Asp Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Met Gly Asp Gly Ala Val Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 931 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 931 ggatacacct tcaccggcta ctat 24 <210> 932 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 932 Gly Tyr Thr Phe Thr Gly Tyr Tyr 1 5 <210> 933 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 933 atcaacccta acagtgatgt caca 24 <210> 934 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 934 Ile Asn Pro Asn Ser Asp Val Thr 1 5 <210> 935 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 935 gcgagaatgg gggacggtgc agtgtttgac tac 33 <210> 936 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 936 Ala Arg Met Gly Asp Gly Ala Val Phe Asp Tyr 1 5 10 <210> 937 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 937 gacatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca acgcattagc agctatttaa attggtatca acagaaacca 120 gggaaagccc ctaaggtgct gatctctgtt gcatccagtt tacaaagtgg ggtcccatca 180 aggttcagtg gcagtggatt tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaggattctg catcttacta ctgtcaacag agttacaata ccccgctcac tttcggcggc 300 gggaccaagc tggagatcaa acga 324 <210> 938 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 938 Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Arg Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45 Ser Val Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ser Ala Ser Tyr Tyr Cys Gln Gln Ser Tyr Asn Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 939 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 939 caacgcatta gcagctat 18 <210> 940 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 940 Gln Arg Ile Ser Ser Tyr 1 5 <210> 941 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 941 gttgcatcc 9 <210> 942 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 942 Val Ala Ser One <210> 943 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 943 caacagagtt acaatacccc gctcact 27 <210> 944 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 944 Gln Gln Ser Tyr Asn Thr Pro Leu Thr 1 5 <210> 945 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 945 gaggtgcagc tggtggagtc tggggctgaa gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaaga cttctggata cagtttcatt ggctattata tacactggat gcgacaggcc 120 cctggacaag ggcttgaatg gatgggatgg atcaacccta agagtggtgt cacaaattat 180 gcacagaggt ttcagggcag ggtcaccatg accagggaca cgtccatcag tactgcctac 240 atggaactga gcaggctgaa atctgacgac acggccgtgt atttctgtgc gagaatgggg 300 gacggtgcag tgtttgactt ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 946 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 946 Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Ser Phe Ile Gly Tyr 20 25 30 Tyr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Lys Ser Gly Val Thr Asn Tyr Ala Gln Arg Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Lys Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Met Gly Asp Gly Ala Val Phe Asp Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 947 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 947 ggatacagtt tcattggcta ttat 24 <210> 948 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 948 Gly Tyr Ser Phe Ile Gly Tyr Tyr 1 5 <210> 949 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 949 atcaacccta agagtggtgt caca 24 <210> 950 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 950 Ile Asn Pro Lys Ser Gly Val Thr 1 5 <210> 951 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 951 gcgagaatgg gggacggtgc agtgtttgac ttc 33 <210> 952 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 952 Ala Arg Met Gly Asp Gly Ala Val Phe Asp Phe 1 5 10 <210> 953 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 953 gacatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gaggattagc agctttttaa attggtatca gcagaaacca 120 gggaaagtcc ctaagctcct gatctatact gcatccaatt tacaaaatgg ggtcccatca 180 aggttcagtg gcactggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag agttacagga ccccgctcac tttcggcgga 300 gggaccaaag tggatatcaa acga 324 <210> 954 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 954 Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Arg Ile Ser Ser Phe 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile 35 40 45 Tyr Thr Ala Ser Asn Leu Gln Asn Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Thr Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Arg Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys Arg 100 105 <210> 955 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 955 cagaggatta gcagcttt 18 <210> 956 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 956 Gln Arg Ile Ser Ser Phe 1 5 <210> 957 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 957 actgcatcc 9 <210> 958 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 958 Thr Ala Ser One <210> 959 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 959 caacagagtt acaggacccc gctcact 27 <210> 960 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 960 Gln Gln Ser Tyr Arg Thr Pro Leu Thr 1 5 <210> 961 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 961 gaggtgcagc tggtggagtc tggggctgaa gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaaga cttctggata caccttcacc ggctactata tgcactggat acgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcaacccta aaagtggtgg cacaaattat 180 gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240 atggaactga gcaggctgag atccgacgac atggccgtgt attattgtgc gagaatgggg 300 gacggtgcag tgtttgactt ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 962 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 962 Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr Met His Trp Ile Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Lys Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Met Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Met Gly Asp Gly Ala Val Phe Asp Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 963 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 963 ggatacacct tcaccggcta ctat 24 <210> 964 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 964 Gly Tyr Thr Phe Thr Gly Tyr Tyr 1 5 <210> 965 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 965 atcaacccta aaagtggtgg caca 24 <210> 966 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 966 Ile Asn Pro Lys Ser Gly Gly Thr 1 5 <210> 967 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 967 gcgagaatgg gggacggtgc agtgtttgac ttc 33 <210> 968 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 968 Ala Arg Met Gly Asp Gly Ala Val Phe Asp Phe 1 5 10 <210> 969 <211> 327 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 969 gacatcgtga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag agttacagta cccctccgct cactttcggc 300 ggagggacca aagtggatat caaacga 327 <210> 970 <211> 109 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 970 Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys Arg 100 105 <210> 971 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 971 cagagcatta gcagctat 18 <210> 972 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 972 Gln Ser Ile Ser Ser Tyr 1 5 <210> 973 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 973 gctgcatcc 9 <210> 974 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 974 Ala Ala Ser One <210> 975 <211> 30 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 975 caacagagtt acagtacccc tccgctcact 30 <210> 976 <211> 10 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 976 Gln Gln Ser Tyr Ser Thr Pro Pro Leu Thr 1 5 10 <210> 977 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 977 caggttcagc tggtgcagtc tgggactgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg cttctggata caccttcacc ggctactata tgcactgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtgatgt cacaaactat 180 gcacagaagt ttcagggcag ggtcaccttg accagggaca cgtccatcag tacagcctac 240 attgacctga gcaggctgag atctgacgac acggccattt attactgtgc gagaatgggg 300 gacggtgcag tgtttgacta ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 978 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 978 Gln Val Gln Leu Val Gln Ser Gly Thr Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Asn Ser Asp Val Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Leu Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Ile Asp Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Met Gly Asp Gly Ala Val Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 979 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 979 ggatacacct tcaccggcta ctat 24 <210> 980 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 980 Gly Tyr Thr Phe Thr Gly Tyr Tyr 1 5 <210> 981 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 981 atcaacccta acagtgatgt caca 24 <210> 982 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 982 Ile Asn Pro Asn Ser Asp Val Thr 1 5 <210> 983 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 983 gcgagaatgg gggacggtgc agtgtttgac tac 33 <210> 984 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 984 Ala Arg Met Gly Asp Gly Ala Val Phe Asp Tyr 1 5 10 <210> 985 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 985 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gcgcattagc agctatttaa attggtatca gcagaaacca 120 gggaaagccc ctaaggtgct gatctctgtt gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccattagtag tctgcaacct 240 gaggattttg catcttacta ctgtcaacag agttacaata ccccgctcac tttcggcgga 300 gggaccaagg tggagatcaa acga 324 <210> 986 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 986 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Arg Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45 Ser Val Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Ser Tyr Asn Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 987 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 987 cagcgcatta gcagctat 18 <210> 988 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 988 Gln Arg Ile Ser Ser Tyr 1 5 <210> 989 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 989 gttgcatcc 9 <210> 990 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 990 Val Ala Ser One <210> 991 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 991 caacagagtt acaatacccc gctcact 27 <210> 992 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 992 Gln Gln Ser Tyr Asn Thr Pro Leu Thr 1 5 <210> 993 <211> 381 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 993 caggtgcagc tggtgcagtc tgggggaggc ttggtcaagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagt agctatgaca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtttcatac attagtagta gtggtaatac catacattac 180 gcagactctg tgaagggccg attcaccatc tccagagaca attccaagaa ctcactttat 240 ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gaaagccggt 300 cccgctacgg tgacacggag gtactactac tactacggtt tggacgtctg gggccaaggg 360 accacggtca ccgtctcctc a 381 <210> 994 <211> 127 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 994 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Asn Thr Ile His Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ala Gly Pro Ala Thr Val Thr Arg Arg Tyr Tyr Tyr Tyr Tyr 100 105 110 Gly Leu Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 995 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 995 ggattcacct tcagtagcta tgac 24 <210> 996 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 996 Gly Phe Thr Phe Ser Ser Tyr Asp 1 5 <210> 997 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 997 attagtagta gtggtaatac cata 24 <210> 998 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 998 Ile Ser Ser Ser Gly Asn Thr Ile 1 5 <210> 999 <211> 60 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 999 gcgaaagccg gtcccgctac ggtgacacgg aggtactact actactacgg tttggacgtc 60 <210> 1000 <211> 20 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1000 Ala Lys Ala Gly Pro Ala Thr Val Thr Arg Arg Tyr Tyr Tyr Tyr Tyr 1 5 10 15 Gly Leu Asp Val 20 <210> 1001 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1001 gacatcgtga tgacccagtc tccatcctcc ctgtctgcat ctgtacgaga cagagtcacc 60 atcacttgcc gggcaagtca gagaattagc agctatttaa attggtttca gcagaaacca 120 gggaaagccc ctaaggtcct gatctatact gcatccagtt tgcaaaatgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagactttg caacttacta ctgtcagcag agttacagga ccccgctcac tttcggcgga 300 gggaccaagg tggagatcaa acga 324 <210> 1002 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1002 Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Arg 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Arg Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45 Tyr Thr Ala Ser Ser Leu Gln Asn Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Arg Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 1003 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1003 cagagaatta gcagctat 18 <210> 1004 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1004 Gln Arg Ile Ser Ser Tyr 1 5 <210> 1005 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1005 actgcatcc 9 <210> 1006 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1006 Thr Ala Ser One <210> 1007 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1007 cagcagagtt acaggacccc gctcact 27 <210> 1008 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1008 Gln Gln Ser Tyr Arg Thr Pro Leu Thr 1 5 <210> 1009 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1009 caggtgcagc tggtacagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg cttctggata cacattcatc ggctactata tgcactgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcaacccta aaagtggtgg cacaaactat 180 gcacagaagt ttcagggcag ggtcaccatg accggggaca cgtccatcag cacagcctac 240 atggagctga gcaggctgag atctgacgac acggccgtgt tttactgtgc gagaatgggg 300 gacggtgcaa tgtttgacta ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 1010 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1010 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ile Gly Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Lys Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Phe Tyr Cys 85 90 95 Ala Arg Met Gly Asp Gly Ala Met Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 1011 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1011 ggatacacat tcatcggcta ctat 24 <210> 1012 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1012 Gly Tyr Thr Phe Ile Gly Tyr Tyr 1 5 <210> 1013 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1013 atcaacccta aaagtggtgg caca 24 <210> 1014 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1014 Ile Asn Pro Lys Ser Gly Gly Thr 1 5 <210> 1015 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1015 gcgagaatgg gggacggtgc aatgtttgac tac 33 <210> 1016 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1016 Ala Arg Met Gly Asp Gly Ala Met Phe Asp Tyr 1 5 10 <210> 1017 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1017 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gagaattagc agctatttaa attggtatca gcagaaagca 120 gggaaagccc ctaaggtcct gatctatact gcatccagtt tgcaaagtgg ggtcccatca 180 cgattcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag agttacagta ccccgctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 1018 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1018 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Arg Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Ala Gly Lys Ala Pro Lys Val Leu Ile 35 40 45 Tyr Thr Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 1019 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1019 cagagaatta gcagctat 18 <210> 1020 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1020 Gln Arg Ile Ser Ser Tyr 1 5 <210> 1021 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1021 actgcatcc 9 <210> 1022 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1022 Thr Ala Ser One <210> 1023 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1023 caacagagtt acagtacccc gctcact 27 <210> 1024 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1024 Gln Gln Ser Tyr Ser Thr Pro Leu Thr 1 5 <210> 1025 <211> 375 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1025 caggtgcagc tggtacagtc tgggggaggc gtggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccgtcaagct 120 ccagggaagg gtctggagtg ggtctctctt attagtgggg atggtggtag cacatactat 180 gcagactctg tgaagggccg attcaccatc tccagagaca acagcaaaaa ctccctgtat 240 ctgcaaatga acagtctgag aactgaggac accgccttgt attactgtgc aaaagatgat 300 agcagctcgt cctggtacta ctactactac ggtatggacg tctggggccg agggaccacg 360 gtcaccgtct cctca 375 <210> 1026 <211> 125 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1026 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Leu Ile Ser Gly Asp Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Asp Ser Ser Ser Ser Trp Tyr Tyr Tyr Tyr Tyr Gly Met 100 105 110 Asp Val Trp Gly Arg Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 1027 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1027 ggattcacct ttgatgatta tgcc 24 <210> 1028 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1028 Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <210> 1029 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1029 attagtgggg atggtggtag caca 24 <210> 1030 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1030 Ile Ser Gly Asp Gly Gly Ser Thr 1 5 <210> 1031 <211> 54 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1031 gcaaaagatg atagcagctc gtcctggtac tactactact acggtatgga cgtc 54 <210> 1032 <211> 18 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1032 Ala Lys Asp Asp Ser Ser Ser Ser Trp Tyr Tyr Tyr Tyr Tyr Gly Met 1 5 10 15 Asp Val <210> 1033 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1033 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gcgcattagc agctatttaa attggtatca gcagaaacca 120 gggaaagccc ctaaggtgct gatctctgtt gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaggattttg catcttacta ctgtcaacag agttacaata ccccgctcac tttcggcgga 300 gggaccaagg tggagatcaa acga 324 <210> 1034 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1034 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Arg Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45 Ser Val Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Ser Tyr Asn Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 1035 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1035 cagcgcatta gcagctat 18 <210> 1036 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1036 Gln Arg Ile Ser Ser Tyr 1 5 <210> 1037 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1037 gttgcatcc 9 <210> 1038 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1038 Val Ala Ser One <210> 1039 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1039 caacagagtt acaatacccc gctcact 27 <210> 1040 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1040 Gln Gln Ser Tyr Asn Thr Pro Leu Thr 1 5 <210> 1041 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1041 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttggt gattatacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctccgat attagttgga atagtggtag caaagactat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctctat 240 cttcaaatga acagtctgag aactgaggat acggcctttt attactgtgc aaaagatagt 300 aggggctacg gtctctacta ccacctcggt ttggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 1042 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1042 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Asn Ser Gly Ser Lys Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Phe Tyr Tyr Cys 85 90 95 Ala Lys Asp Ser Arg Gly Tyr Gly Leu Tyr Tyr His Leu Gly Leu Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1043 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1043 ggattcacct ttggtgatta tacc 24 <210> 1044 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1044 Gly Phe Thr Phe Gly Asp Tyr Thr 1 5 <210> 1045 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1045 attagttgga attagtggtag caaa 24 <210> 1046 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1046 Ile Ser Trp Asn Ser Gly Ser Lys 1 5 <210> 1047 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1047 gcaaaagata gtaggggcta cggtctctac taccacctcg gtttggacgt c 51 <210> 1048 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1048 Ala Lys Asp Ser Arg Gly Tyr Gly Leu Tyr Tyr His Leu Gly Leu Asp 1 5 10 15 Val <210> 1049 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1049 gaggtgcagc tggtggagtc tgggggaggc ttggtgcagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgct gattatacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcagat attagttgga atagtggtag tatagcctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctctat 240 cttcaaatga acagtctgag aactgaggac acggcctttt attactgtgc aaaagatagt 300 aggggctacg gtcactataa gtacctcggt ttggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 1050 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1050 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Asn Ser Gly Ser Ile Ala Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Phe Tyr Tyr Cys 85 90 95 Ala Lys Asp Ser Arg Gly Tyr Gly His Tyr Lys Tyr Leu Gly Leu Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1051 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1051 ggattcacct ttgctgatta tacc 24 <210> 1052 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1052 Gly Phe Thr Phe Ala Asp Tyr Thr 1 5 <210> 1053 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1053 attagttgga attagtggtag tata 24 <210> 1054 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1054 Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <210> 1055 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1055 gcaaaagata gtaggggcta cggtcactat aagtacctcg gtttggacgt c 51 <210> 1056 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1056 Ala Lys Asp Ser Arg Gly Tyr Gly His Tyr Lys Tyr Leu Gly Leu Asp 1 5 10 15 Val <210> 1057 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1057 gaggtgcagc tggtggagtc tgggggaggc atggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt ccccttcaat gattacacca tgcactgggt ccggcaagtc 120 ccagggaggg gcctggagtg ggtctcagat attagttgga atagcggcag taaaggctat 180 gcggactctg tgaagggtcg attcatcatc tccagagaca acgccaagaa ctccctgtac 240 ctgcaaatga acagtctgag agttgaagac acggccttgt attactgtgt aaaagatgga 300 agtggctacg ggaggttcca ttattacgct atggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 1058 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1058 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Met Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Phe Asn Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Val Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Asn Ser Gly Ser Lys Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Val Lys Asp Gly Ser Gly Tyr Gly Arg Phe His Tyr Tyr Ala Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1059 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1059 ggattcccct tcaatgatta cacc 24 <210> 1060 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1060 Gly Phe Pro Phe Asn Asp Tyr Thr 1 5 <210> 1061 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1061 attagttgga atagcggcag taaa 24 <210> 1062 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1062 Ile Ser Trp Asn Ser Gly Ser Lys 1 5 <210> 1063 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1063 gtaaaagatg gaagtggcta cgggaggttc cattattacg ctatggacgt c 51 <210> 1064 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1064 Val Lys Asp Gly Ser Gly Tyr Gly Arg Phe His Tyr Tyr Ala Met Asp 1 5 10 15 Val <210> 1065 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1065 gaggtgcagc tggtggagtc tggtggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgct gattatacca tgcactgggt ccgccaagtt 120 ccagggaagg gcctggagtg ggtctcagat attagttgga atagtggtag caaagactat 180 gcggactctg tgaagggccg cttcaccatc tccagagaca acgccaagaa tttcctgtat 240 ctgcaaatga acagtctgag agctgaagac acggccttgt attactgtgt aaaatatgga 300 agtggctacg ggaaattcta cttctacgct atggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 1066 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1066 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Asn Ser Gly Ser Lys Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Phe Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Val Lys Tyr Gly Ser Gly Tyr Gly Lys Phe Tyr Phe Tyr Ala Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1067 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1067 ggattcacct ttgctgatta tacc 24 <210> 1068 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1068 Gly Phe Thr Phe Ala Asp Tyr Thr 1 5 <210> 1069 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1069 attagttgga attagtggtag caaa 24 <210> 1070 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1070 Ile Ser Trp Asn Ser Gly Ser Lys 1 5 <210> 1071 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1071 gtaaaatatg gaagtggcta cgggaaattc tacttctacg ctatggacgt c 51 <210> 1072 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1072 Val Lys Tyr Gly Ser Gly Tyr Gly Lys Phe Tyr Phe Tyr Ala Met Asp 1 5 10 15 Val <210> 1073 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1073 gaggtgcagc tggtgcagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgct gattatacca tgcactgggt ccggcaaact 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag caaagactat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag aactgaggac acggccttgt attactgtgc aaaatatgga 300 agtggctacg ggagatattt cttctacgct atggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 1074 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1074 Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Lys Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Tyr Gly Ser Gly Tyr Gly Arg Tyr Phe Phe Tyr Ala Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1075 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1075 ggattcacct ttgctgatta tacc 24 <210> 1076 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1076 Gly Phe Thr Phe Ala Asp Tyr Thr 1 5 <210> 1077 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1077 attagttgga attagtggtag caaa 24 <210> 1078 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1078 Ile Ser Trp Asn Ser Gly Ser Lys 1 5 <210> 1079 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1079 gcaaaatatg gaagtggcta cgggagatat ttcttctacg ctatggacgt c 51 <210> 1080 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1080 Ala Lys Tyr Gly Ser Gly Tyr Gly Arg Tyr Phe Phe Tyr Ala Met Asp 1 5 10 15 Val <210> 1081 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1081 gaggtgcagc tggtggagtc aaggggagcc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cgcctttaat gattatacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcagat attagttgga atagtaatag taaagactat 180 gcggactctg tgaagggccg attcaccatc tccagagaca atgccaagaa ctccctctat 240 ctacaaatga acagtctgag agctgaggac acggccttgt attactgtgt aaaagatgga 300 agtggctacg ggaaattttc cctctacgct ttggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 1082 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1082 Glu Val Gln Leu Val Glu Ser Arg Gly Ala Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Asn Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Asn Ser Asn Ser Lys Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Val Lys Asp Gly Ser Gly Tyr Gly Lys Phe Ser Leu Tyr Ala Leu Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1083 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1083 ggattcgcct ttaatgatta tacc 24 <210> 1084 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1084 Gly Phe Ala Phe Asn Asp Tyr Thr 1 5 <210> 1085 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1085 attagttgga attagtaatag taaa 24 <210> 1086 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1086 Ile Ser Trp Asn Ser Asn Ser Lys 1 5 <210> 1087 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1087 gtaaaagatg gaagtggcta cgggaaattt tccctctacg ctttggacgt c 51 <210> 1088 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1088 Val Lys Asp Gly Ser Gly Tyr Gly Lys Phe Ser Leu Tyr Ala Leu Asp 1 5 10 15 Val <210> 1089 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1089 caggtgcagc tggtggagtc tgggggaggc ttggttcacc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt caaatttgat gattatacca tgcactgggt ccggcaagct 120 ccagggaagg gcctagagtg ggtctcagat attagttgga atagtggtag taaaggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagga ttccctatat 240 ctgcagatgg acagtctgag agctgcagac acggccttct attactgtgc aaaagataaa 300 agtggctacg gccacttcta ctactacgct atggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 1090 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1090 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val His Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Asn Ser Gly Ser Lys Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asp Ser Leu Tyr 65 70 75 80 Leu Gln Met Asp Ser Leu Arg Ala Ala Asp Thr Ala Phe Tyr Tyr Cys 85 90 95 Ala Lys Asp Lys Ser Gly Tyr Gly His Phe Tyr Tyr Tyr Ala Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1091 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1091 ggattcaaat ttgatgatta tacc 24 <210> 1092 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1092 Gly Phe Lys Phe Asp Asp Tyr Thr 1 5 <210> 1093 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1093 attagttgga attagtggtag taaa 24 <210> 1094 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1094 Ile Ser Trp Asn Ser Gly Ser Lys 1 5 <210> 1095 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1095 gcaaaagata aaagtggcta cggccacttc tactactacg ctatggacgt c 51 <210> 1096 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1096 Ala Lys Asp Lys Ser Gly Tyr Gly His Phe Tyr Tyr Tyr Ala Met Asp 1 5 10 15 Val <210> 1097 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1097 gaggtgcagc tggtggagtc tgggggaggc ttggtacacc ctggcaggtc cctaagactc 60 tcctgtacag cctctggatt caagtttgct gattatacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcagat attagttgga atagtggtag taaaggctat 180 gcggactctg taaagggccg attcaccatc tccagagaca atgacaagaa ctccctgtat 240 ctgcaaatga acagtctgag aggtgaggac acggccttgt attactgtgc aaaagatgga 300 agtggctacg ggaggttcca cttctacgct atcgacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 1098 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1098 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val His Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Lys Phe Ala Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Asn Ser Gly Ser Lys Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Asp Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Gly Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Gly Ser Gly Tyr Gly Arg Phe His Phe Tyr Ala Ile Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1099 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1099 ggattcaagt ttgctgatta tacc 24 <210> 1100 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1100 Gly Phe Lys Phe Ala Asp Tyr Thr 1 5 <210> 1101 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1101 attagttgga attagtggtag taaa 24 <210> 1102 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1102 Ile Ser Trp Asn Ser Gly Ser Lys 1 5 <210> 1103 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1103 gcaaaagatg gaagtggcta cgggaggttc cacttctacg ctatcgacgt c 51 <210> 1104 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1104 Ala Lys Asp Gly Ser Gly Tyr Gly Arg Phe His Phe Tyr Ala Ile Asp 1 5 10 15 Val <210> 1105 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1105 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgtag cctctggatt cacctttgat gattattcca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag caaagactat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag agctgaagac acggccttgt attactgtgc aaaatatgga 300 agtggctacg ggaagttcta ccactacggt ttggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 1106 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1106 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Lys Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Tyr Gly Ser Gly Tyr Gly Lys Phe Tyr His Tyr Gly Leu Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1107 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1107 ggattcacct ttgatgatta ttcc 24 <210> 1108 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1108 Gly Phe Thr Phe Asp Asp Tyr Ser 1 5 <210> 1109 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1109 attagttgga attagtggtag caaa 24 <210> 1110 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1110 Ile Ser Trp Asn Ser Gly Ser Lys 1 5 <210> 1111 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1111 gcaaaatatg gaagtggcta cgggaagttc taccactacg gtttggacgt c 51 <210> 1112 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1112 Ala Lys Tyr Gly Ser Gly Tyr Gly Lys Phe Tyr His Tyr Gly Leu Asp 1 5 10 15 Val <210> 1113 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1113 caggtgcagt tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgct gattatacca tgcactgggt ccggcaggct 120 ccagggaagg gcctggagtg ggtctcagat attagttgga atagtggtag catgggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa atccctgtat 240 ctgcaaatga acagtctgag aactgaggac acggccttgt attactgtgc aaaagatgga 300 agtggctacg ggaaatactt cttctacgct atggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 1114 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1114 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Asn Ser Gly Ser Met Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Gly Ser Gly Tyr Gly Lys Tyr Phe Phe Tyr Ala Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1115 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1115 ggattcacct ttgctgatta tacc 24 <210> 1116 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1116 Gly Phe Thr Phe Ala Asp Tyr Thr 1 5 <210> 1117 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1117 attagttgga atagtggtag catg 24 <210> 1118 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1118 Ile Ser Trp Asn Ser Gly Ser Met 1 5 <210> 1119 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1119 gcaaaagatg gaagtggcta cgggaaatac ttcttctacg ctatggacgt c 51 <210> 1120 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1120 Ala Lys Asp Gly Ser Gly Tyr Gly Lys Tyr Phe Phe Tyr Ala Met Asp 1 5 10 15 Val <210> 1121 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1121 gaggtgcagc tggtgcagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt caccttttct gattatacta tgcattgggt ccggcaaggt 120 ccagggaagg gcctggagtg ggtctcagat attagttgga atagtggtag taaaggctat 180 acggactctg tgaagggccg attcaccatt tccagagaca acgccaagaa gtccctgtat 240 ctacaaatga acagtctgag agctgaggac acggccttgt actactgtgt aaaagatgga 300 agtggctacg ggaaatacca cttctacgct atggacgtct ggggccaagg gaccctggtc 360 accgtctcct ca 372 <210> 1122 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1122 Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Asn Ser Gly Ser Lys Gly Tyr Thr Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Val Lys Asp Gly Ser Gly Tyr Gly Lys Tyr His Phe Tyr Ala Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 1123 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1123 ggattcacct tttctgatta tact 24 <210> 1124 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1124 Gly Phe Thr Phe Ser Asp Tyr Thr 1 5 <210> 1125 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1125 attagttgga attagtggtag taaa 24 <210> 1126 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1126 Ile Ser Trp Asn Ser Gly Ser Lys 1 5 <210> 1127 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1127 gtaaaagatg gaagtggcta cgggaaatac cacttctacg ctatggacgt c 51 <210> 1128 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1128 Val Lys Asp Gly Ser Gly Tyr Gly Lys Tyr His Phe Tyr Ala Met Asp 1 5 10 15 Val <210> 1129 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1129 gaggtgcagc tggtggagtc ggggggaggc ttggttcacc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggaatg ggtctcagat attagttgga atagtggtag cagaggctat 180 gcggactctg tgaagggccg attcaccatc tccagagata atgccgagaa ctccctgtac 240 ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagataaa 300 agtggctacg gccactacta ctactacgct atggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 1130 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1130 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val His Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Asn Ser Gly Ser Arg Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Lys Ser Gly Tyr Gly His Tyr Tyr Tyr Tyr Ala Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1131 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1131 ggattcacct ttgatgatta tacc 24 <210> 1132 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1132 Gly Phe Thr Phe Asp Asp Tyr Thr 1 5 <210> 1133 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1133 attagttgga attagtggtag caga 24 <210> 1134 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1134 Ile Ser Trp Asn Ser Gly Ser Arg 1 5 <210> 1135 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1135 gcaaaagata aaagtggcta cggccactac tactactacg ctatggacgt c 51 <210> 1136 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1136 Ala Lys Asp Lys Ser Gly Tyr Gly His Tyr Tyr Tyr Tyr Ala Met Asp 1 5 10 15 Val <210> 1137 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1137 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcgggtc cctgagactc 60 tcctgtgaag cctctggatt cacctttgct gattatacct tgcactgggt ccggcaagct 120 ccagggaagg gcctggaatg ggtctcagat attagttgga atagtggcac cagaggctat 180 gcggactctg tgaggggccg attcaccatc tccagagaca acgccaagaa gtccctgtat 240 ctgcaaatga acagtctgag atctgaggac acggccttgt attactgtgt gaaagatgga 300 agtggctacg ggagatataa tttctacgct atggacgtct ggggccaagg gaccacggtc 360 accgtctcct ca 372 <210> 1138 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1138 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ala Asp Tyr 20 25 30 Thr Leu His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Asn Ser Gly Thr Arg Gly Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Val Lys Asp Gly Ser Gly Tyr Gly Arg Tyr Asn Phe Tyr Ala Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1139 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1139 ggattcacct ttgctgatta tacc 24 <210> 1140 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1140 Gly Phe Thr Phe Ala Asp Tyr Thr 1 5 <210> 1141 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1141 attagttgga atagtggcac caga 24 <210> 1142 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1142 Ile Ser Trp Asn Ser Gly Thr Arg 1 5 <210> 1143 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1143 gtgaaagatg gaagtggcta cgggagatat aatttctacg ctatggacgt c 51 <210> 1144 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1144 Val Lys Asp Gly Ser Gly Tyr Gly Arg Tyr Asn Phe Tyr Ala Met Asp 1 5 10 15 Val <210> 1145 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1145 gaggtgcagc tggtggagtc tgggggaggc ttggttcagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt tacctttgct gactatacca tgcactgggt ccggcaaggt 120 ccagggaagg gcctggagtg ggtctcagat attggttgga atagtaatac tataggctat 180 gcggactctg tgaagggccg attcgccatc tccagagaca acgccaagaa ctccctgtat 240 cttcaaatga acagtctgcg acctgaggac acggccttat attactgtgt aaaggataaa 300 agtggctacg ggaaattcca atacggtttg gacgtctggg gccaagggac cacggtcacc 360 gtctcctca 369 <210> 1146 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1146 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Gly Trp Asn Ser Asn Thr Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Val Lys Asp Lys Ser Gly Tyr Gly Lys Phe Gln Tyr Gly Leu Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1147 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1147 ggatttacct ttgctgacta tacc 24 <210> 1148 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1148 Gly Phe Thr Phe Ala Asp Tyr Thr 1 5 <210> 1149 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1149 attggttgga atagtaatac tata 24 <210> 1150 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1150 Ile Gly Trp Asn Ser Asn Thr Ile 1 5 <210> 1151 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1151 gtaaaggata aaagtggcta cgggaaattc caatacggtt tggacgtc 48 <210> 1152 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1152 Val Lys Asp Lys Ser Gly Tyr Gly Lys Phe Gln Tyr Gly Leu Asp Val 1 5 10 15 <210> 1153 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1153 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt tacatttgac gattatacca tgcactgggt ccggcaaggt 120 ccagggaagg gcctggagtg ggtctcagat attggttgga atagtaacag tataggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctccaaatga acagtctgag acctgaggac acggccttgt atttctgtgt aaaggataaa 300 agtggctacg ggaaattttt catcggtttg gacgtctggg gccaagggac aatggtcacc 360 gtctcttca 369 <210> 1154 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1154 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Gly Trp Asn Ser Asn Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Phe Cys 85 90 95 Val Lys Asp Lys Ser Gly Tyr Gly Lys Phe Phe Ile Gly Leu Asp Val 100 105 110 Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 1155 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1155 ggatttacat ttgacgatta tacc 24 <210> 1156 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1156 Gly Phe Thr Phe Asp Asp Tyr Thr 1 5 <210> 1157 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1157 attggttgga atagtaacag tata 24 <210> 1158 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1158 Ile Gly Trp Asn Ser Asn Ser Ile 1 5 <210> 1159 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1159 gtaaaggata aaagtggcta cgggaaattt ttcatcggtt tggacgtc 48 <210> 1160 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1160 Val Lys Asp Lys Ser Gly Tyr Gly Lys Phe Phe Ile Gly Leu Asp Val 1 5 10 15 <210> 1161 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1161 caggtgcagt tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt tacatttgac gattatacca tgcactgggt ccggcaaggt 120 ccagggaagg gcctggagtg ggtctcagat attggttgga atagtaatac taaaggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ttccctgtat 240 ctccaaatga acagtctgag acctgaggac acggccttgt atttctgtgt gaaggataaa 300 agtggctacg ggaaattttt catcggtttg gacgtctggg gccaagggac aatggtcacc 360 gtctcttca 369 <210> 1162 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1162 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Gly Trp Asn Ser Asn Thr Lys Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Phe Cys 85 90 95 Val Lys Asp Lys Ser Gly Tyr Gly Lys Phe Phe Ile Gly Leu Asp Val 100 105 110 Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 1163 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1163 ggatttacat ttgacgatta tacc 24 <210> 1164 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1164 Gly Phe Thr Phe Asp Asp Tyr Thr 1 5 <210> 1165 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1165 attggttgga atagtaatac taaa 24 <210> 1166 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1166 Ile Gly Trp Asn Ser Asn Thr Lys 1 5 <210> 1167 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1167 gtgaaggata aaagtggcta cgggaaattt ttcatcggtt tggacgtc 48 <210> 1168 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1168 Val Lys Asp Lys Ser Gly Tyr Gly Lys Phe Phe Ile Gly Leu Asp Val 1 5 10 15 <210> 1169 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1169 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctgggcggtc cctgagactc 60 tcctgtgcag cctccggatt cacctttgct gattatacca tgcactgggt ccggcaaggt 120 ccagggacgg gcctggagtg ggtctcagat attggttgga gtggtggtag tttaggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ttggaaatga acaatctgcg acctgaagac acggccttgt attattgtgt aaaggataaa 300 agtggctacg ggaaattcca gtacggtttg gacgtctggg gccaagggac cacggtcacc 360 gtctcctca 369 <210> 1170 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1170 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ala Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Gly Pro Gly Thr Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Gly Trp Ser Gly Gly Ser Leu Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Glu Met Asn Asn Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Val Lys Asp Lys Ser Gly Tyr Gly Lys Phe Gln Tyr Gly Leu Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1171 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1171 ggattcacct ttgctgatta tacc 24 <210> 1172 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1172 Gly Phe Thr Phe Ala Asp Tyr Thr 1 5 <210> 1173 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1173 attggttgga gtggtggtag ttta 24 <210> 1174 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1174 Ile Gly Trp Ser Gly Gly Ser Leu 1 5 <210> 1175 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1175 gtaaaggata aaagtggcta cgggaaattc cagtacggtt tggacgtc 48 <210> 1176 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1176 Val Lys Asp Lys Ser Gly Tyr Gly Lys Phe Gln Tyr Gly Leu Asp Val 1 5 10 15 <210> 1177 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1177 gaggtgcagc tggtggagtc tgggggaggc gtggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctgggtt taaatttgat ggttatacca tgcactgggt ccggcaaggt 120 ccagggaagg gcctggagtg ggtctcagat attggttgga atagtaacac tataggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctccaaatga acagtctgag accagaggac acggccttgt atttctgtgt aaaggataaa 300 agtggctacg ggaaattttt catcggtttg gacgtctggg gccaagggac aatggtcacc 360 gtctcttca 369 <210> 1178 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1178 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Asp Gly Tyr 20 25 30 Thr Met His Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Gly Trp Asn Ser Asn Thr Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Phe Cys 85 90 95 Val Lys Asp Lys Ser Gly Tyr Gly Lys Phe Phe Ile Gly Leu Asp Val 100 105 110 Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 1179 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1179 gggtttaaat ttgatggtta tacc 24 <210> 1180 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1180 Gly Phe Lys Phe Asp Gly Tyr Thr 1 5 <210> 1181 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1181 attggttgga atagtaacac tata 24 <210> 1182 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1182 Ile Gly Trp Asn Ser Asn Thr Ile 1 5 <210> 1183 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1183 gtaaaggata aaagtggcta cgggaaattt ttcatcggtt tggacgtc 48 <210> 1184 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1184 Val Lys Asp Lys Ser Gly Tyr Gly Lys Phe Phe Ile Gly Leu Asp Val 1 5 10 15 <210> 1185 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1185 caggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatacca tgcactgggt ccggcaaggt 120 ccagggaagg gcctggagtg ggtctcagat attggttgga atagtaatac tataggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaggaa ctccctgtat 240 ctgcaaatga acagtctgcg acctgaagac acggccttat attactgtgt aaaggataaa 300 agtggctacg ggaaattcca atacggtttg gacgtctggg gccaagggac cacggtcacc 360 gtctcctca 369 <210> 1186 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1186 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Gly Trp Asn Ser Asn Thr Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Val Lys Asp Lys Ser Gly Tyr Gly Lys Phe Gln Tyr Gly Leu Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1187 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1187 ggattcacct ttgatgatta tacc 24 <210> 1188 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1188 Gly Phe Thr Phe Asp Asp Tyr Thr 1 5 <210> 1189 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1189 attggttgga atagtaatac tata 24 <210> 1190 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1190 Ile Gly Trp Asn Ser Asn Thr Ile 1 5 <210> 1191 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1191 gtaaaggata aaagtggcta cgggaaattc caatacggtt tggacgtc 48 <210> 1192 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1192 Val Lys Asp Lys Ser Gly Tyr Gly Lys Phe Gln Tyr Gly Leu Asp Val 1 5 10 15 <210> 1193 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1193 caggtgcaac tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt caagtttgat gattatacca tgcactgggt ccggcaaggt 120 ccagggaagg gcctggagtg ggtctcagac attagttgga gtggtggtag catagactat 180 acggactctg tgaagggccg attctccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag agttgaagac acggccttgt attattgtgt aaaagataaa 300 agtggctacg ggaagtactc ttacggtttg gacgtctggg gccaagggac cacggtcacc 360 gtctcctca 369 <210> 1194 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1194 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Lys Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Asp Ile Ser Trp Ser Gly Gly Ser Ile Asp Tyr Thr Asp Ser Val 50 55 60 Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Val Lys Asp Lys Ser Gly Tyr Gly Lys Tyr Ser Tyr Gly Leu Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1195 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1195 ggattcaagt ttgatgatta tacc 24 <210> 1196 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1196 Gly Phe Lys Phe Asp Asp Tyr Thr 1 5 <210> 1197 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1197 attagttgga gtggtggtag cata 24 <210> 1198 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1198 Ile Ser Trp Ser Gly Gly Ser Ile 1 5 <210> 1199 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1199 gtaaaagata aaagtggcta cgggaagtac tcttacggtt tggacgtc 48 <210> 1200 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1200 Val Lys Asp Lys Ser Gly Tyr Gly Lys Tyr Ser Tyr Gly Leu Asp Val 1 5 10 15 <210> 1201 <211> 357 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1201 gaggtgcagc tggtggagtc tgggggaggc ttggtaaagc cgggggggtc ccttagaatc 60 tcctgtgcag cctctggatt ctctttcatt aacgcctgga tgaactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggttggccgt attaaaagca taagtgatgg tgggacaaca 180 gactacgctg catccgtgaa aggcagattc accatctcaa gagaagattc aaaaaatatg 240 ctgtttctgg aaatgaatag tctgaaaacc gaggacacag ccgtgtttta ctgtaccaca 300 gaggtcgcta gaactccgaa ctactggggc cggggaaccc tggtcaccgt ctcctca 357 <210> 1202 <211> 119 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1202 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Ile Ser Cys Ala Ala Ser Gly Phe Ser Phe Ile Asn Ala 20 25 30 Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Lys Ser Ile Ser Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Glu Asp Ser Lys Asn Met 65 70 75 80 Leu Phe Leu Glu Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Phe 85 90 95 Tyr Cys Thr Thr Glu Val Ala Arg Thr Pro Asn Tyr Trp Gly Arg Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 1203 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1203 ggattctctt tcattaacgc ctgg 24 <210> 1204 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1204 Gly Phe Ser Phe Ile Asn Ala Trp 1 5 <210> 1205 <211> 30 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1205 attaaaagca taagtgatgg tgggacaaca 30 <210> 1206 <211> 10 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1206 Ile Lys Ser Ile Ser Asp Gly Gly Thr Thr 1 5 10 <210> 1207 <211> 30 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1207 accacagagg tcgctagaac tccgaactac 30 <210> 1208 <211> 10 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1208 Thr Thr Glu Val Ala Arg Thr Pro Asn Tyr 1 5 10 <210> 1209 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1209 gaagtacagc ttgtagaatc cggcggagga ctggtacaac ctggaagaag tcttagactg 60 agttgcgcag ctagtgggtt tacattcgac gattacagca tgcattgggt gaggcaagct 120 cctggtaaag gattggaatg ggttagcggg atatcatgga actcaggaag caagggatac 180 gccgacagcg tgaaaggccg atttacaata tctagggaca acgcaaaaaa ctctctctac 240 cttcaaatga actctcttag ggcagaagac acagcattgt attattgcgc aaaatacggc 300 agtggttatg gcaagtttta tcattatgga ctggacgtgt ggggacaagg gacaacagtg 360 acagtgagta gc 372 <210> 1210 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1210 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Lys Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Tyr Gly Ser Gly Tyr Gly Lys Phe Tyr His Tyr Gly Leu Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1211 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1211 gggtttacat tcgacgatta cagc 24 <210> 1212 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1212 Gly Phe Thr Phe Asp Asp Tyr Ser 1 5 <210> 1213 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1213 atatcatgga actcaggaag caag 24 <210> 1214 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1214 Ile Ser Trp Asn Ser Gly Ser Lys 1 5 <210> 1215 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1215 gcaaaatacg gcagtggtta tggcaagttt tatcattatg gactggacgt g 51 <210> 1216 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1216 Ala Lys Tyr Gly Ser Gly Tyr Gly Lys Phe Tyr His Tyr Gly Leu Asp 1 5 10 15 Val <210> 1217 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1217 gaagtacaac tggtcgaatc tggaggaggt cttgttcaac ctggtcgatc acttcgcctt 60 tcttgtgccg cttctggttt cactttcgac gattatagca tgcattgggt acgacaggct 120 cccggaaaag ggctggaatg ggtgtcagga attagttgga actcaggaag tattggatac 180 gctgattcag tcaaaggacg cttcacaatc tcaagggaca acgctaaaaa ctcactttat 240 ttgcaaatga actctctccg cgctgaagat accgctctct attattgcgc caaagatggg 300 tctggttacg gttattttta ctactatgga atggacgttt ggggccaagg aacaactgtc 360 acagtatcat cc 372 <210> 1218 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1218 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Gly Ser Gly Tyr Gly Tyr Phe Tyr Tyr Tyr Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1219 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1219 ggtttcactt tcgacgatta tagc 24 <210> 1220 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1220 Gly Phe Thr Phe Asp Asp Tyr Ser 1 5 <210> 1221 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1221 attagttgga actcaggaag tatt 24 <210> 1222 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1222 Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <210> 1223 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1223 gccaaagatg ggtctggtta cggttatttt tactactatg gaatggacgt t 51 <210> 1224 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1224 Ala Lys Asp Gly Ser Gly Tyr Gly Tyr Phe Tyr Tyr Tyr Gly Met Asp 1 5 10 15 Val <210> 1225 <211> 372 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1225 gaagtgcaac tcgttgaaag cggaggagga ctggtccagc ccggcagatc tctcagattg 60 tcttgcgctg catccggatt tacatttgac gactattcaa tgcactgggt acggcaagcc 120 ccaggtaaag gactcgaatg ggtaagcggc atatcttgga actcaggcag tattggctac 180 gcagattcag taaaaggaag attcactatt tcaagggata atgctaagaa cagtctctac 240 ttgcaaatga atagcttgcg cgcagaagat acagcacttt attattgtgc aaaagatgga 300 agcggttatg ggaaatttta ttattatggt atggatgtat ggggtcaagg tacaacagtt 360 actgtgtcaa gt 372 <210> 1226 <211> 124 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1226 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Gly Ser Gly Tyr Gly Lys Phe Tyr Tyr Tyr Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1227 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1227 ggatttacat ttgacgacta ttca 24 <210> 1228 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1228 Gly Phe Thr Phe Asp Asp Tyr Ser 1 5 <210> 1229 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1229 atatcttgga actcaggcag tatt 24 <210> 1230 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1230 Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <210> 1231 <211> 51 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1231 gcaaaagatg gaagcggtta tgggaaattt tattattatg gtatggatgt a 51 <210> 1232 <211> 17 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1232 Ala Lys Asp Gly Ser Gly Tyr Gly Lys Phe Tyr Tyr Tyr Gly Met Asp 1 5 10 15 Val <210> 1233 <211> 324 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1233 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccgtca 180 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240 gaagattttg caacttacta ctgtcaacag agttacagta cccctccgat caccttcggc 300 caagggacac gactggagat taaa 324 <210> 1234 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1234 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 1235 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1235 cagagcatta gcagctat 18 <210> 1236 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1236 Gln Ser Ile Ser Ser Tyr 1 5 <210> 1237 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1237 gctgcatcc 9 <210> 1238 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1238 Ala Ala Ser One <210> 1239 <211> 30 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1239 caacagagtt acagtacccc tccgatcacc 30 <210> 1240 <211> 10 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1240 Gln Gln Ser Tyr Ser Thr Pro Pro Ile Thr 1 5 10 <210> 1241 <211> 382 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1241 gaagtacagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgtag cctctggatt cacctttaat gattatgcca tgcactgggt ccggcaagct 120 ccagggaagg gcctggaatg ggtctcagtt attagttgga atagtgatag cataggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatgc acagtctgag agctgaggac acggccttgt attactgtgc aaaagataat 300 cactatggtt cggggagtta ttactactac caatacggta tggacgtctg gggccaaggg 360 accacggtca ccgtctcctc ag 382 <210> 1242 <211> 127 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1242 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Asn Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Ser Trp Asn Ser Asp Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met His Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Asn His Tyr Gly Ser Gly Ser Tyr Tyr Tyr Tyr Gln Tyr 100 105 110 Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 1243 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1243 ggattcacct ttaatgatta tgcc 24 <210> 1244 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1244 Gly Phe Thr Phe Asn Asp Tyr Ala 1 5 <210> 1245 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1245 attagttgga atagtgatag cata 24 <210> 1246 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1246 Ile Ser Trp Asn Ser Asp Ser Ile 1 5 <210> 1247 <211> 60 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1247 gcaaaagata atcactatgg ttcggggagt tattactact accaatacgg tatggacgtc 60 <210> 1248 <211> 20 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1248 Ala Lys Asp Asn His Tyr Gly Ser Gly Ser Tyr Tyr Tyr Tyr Gln Tyr 1 5 10 15 Gly Met Asp Val 20 <210> 1249 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1249 gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag tataggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa gtccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagataat 300 agtggctacg gtcactacta ctacggaatg gacgtctggg gccaagggac cacggtcacc 360 gtcgcctca 369 <210> 1250 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1250 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Asn Ser Gly Tyr Gly His Tyr Tyr Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ala Ser 115 120 <210> 1251 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1251 ggattcacct ttgatgatta tacc 24 <210> 1252 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1252 Gly Phe Thr Phe Asp Asp Tyr Thr 1 5 <210> 1253 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1253 attagttgga attagtggtag tata 24 <210> 1254 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1254 Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <210> 1255 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1255 gcaaaagata atagtggcta cggtcactac tactacggaa tggacgtc 48 <210> 1256 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1256 Ala Lys Asp Asn Ser Gly Tyr Gly His Tyr Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 1257 <211> 320 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1257 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca gcaaaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240 gaagattttg cagtttatta ctgtcagcac tatattaact ggcctctcac tttcggcgga 300 gggaccaagg tggagatcaa 320 <210> 1258 <211> 108 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1258 Ala Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro 1 5 10 15 Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser 20 25 30 Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln 65 70 75 80 Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Ile Asn Trp Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 1259 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1259 cagagtgtta gcagcaac 18 <210> 1260 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1260 Gln Ser Val Ser Ser Asn 1 5 <210> 1261 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1261 ggtgcatcc 9 <210> 1262 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1262 Gly Ala Ser One <210> 1263 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1263 cagcactata ttaactggcc tctcact 27 <210> 1264 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1264 Gln His Tyr Ile Asn Trp Pro Leu Thr 1 5 <210> 1265 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1265 gaagtgcaac tggtggagtc tgggggaggc ttagtacagc ctggcgggtc cctgagactc 60 tcctgtgcag ccactggatt cacctttgat gattttacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt atcagttgga atagtggtag cataggctat 180 gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggccttgt actactgtgc aaaagataat 300 agtggctacg gctattatta ctacggtatg gacgtctggg gccaagggac cacggtcacc 360 gtctcctca 369 <210> 1266 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1266 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Thr Gly Phe Thr Phe Asp Asp Phe 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Asn Ser Gly Tyr Gly Tyr Tyr Tyr Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1267 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1267 ggattcacct ttgatgattt tacc 24 <210> 1268 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1268 Gly Phe Thr Phe Asp Asp Phe Thr 1 5 <210> 1269 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1269 atcagttgga atagtggtag cata 24 <210> 1270 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1270 Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <210> 1271 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1271 gcaaaagata atagtggcta cggctattat tactacggta tggacgtc 48 <210> 1272 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1272 Ala Lys Asp Asn Ser Gly Tyr Gly Tyr Tyr Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 1273 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1273 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca cagtgttagc aggaactcag cctggtacca gcagaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180 aggttcagtg gcagtgggtc tgggacagaa ttcactctca ccatcagcag cctgcagtct 240 gaagattttg caattttatta ctgtcagcag tataataatt ggcctctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 1274 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1274 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser His Ser Val Ser Arg Asn 20 25 30 Ser Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Ile Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 1275 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1275 cacagtgtta gcaggaac 18 <210> 1276 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1276 His Ser Val Ser Arg Asn 1 5 <210> 1277 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1277 ggtgcatcc 9 <210> 1278 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1278 Gly Ala Ser One <210> 1279 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1279 cagcagtata ataattggcc tctcact 27 <210> 1280 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1280 Gln Gln Tyr Asn Asn Trp Pro Leu Thr 1 5 <210> 1281 <211> 369 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1281 gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag tataggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa gtccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagataat 300 agtggctacg gtcactacta ctacggaatg gacgtctggg gccaagggac cacggtcacc 360 gtcgcctca 369 <210> 1282 <211> 123 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1282 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Asn Ser Gly Tyr Gly His Tyr Tyr Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ala Ser 115 120 <210> 1283 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1283 ggattcacct ttgatgatta tacc 24 <210> 1284 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1284 Gly Phe Thr Phe Asp Asp Tyr Thr 1 5 <210> 1285 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1285 attagttgga attagtggtag tata 24 <210> 1286 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1286 Ile Ser Trp Asn Ser Gly Ser Ile 1 5 <210> 1287 <211> 48 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1287 gcaaaagata atagtggcta cggtcactac tactacggaa tggacgtc 48 <210> 1288 <211> 16 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1288 Ala Lys Asp Asn Ser Gly Tyr Gly His Tyr Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 1289 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1289 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca gcaaaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240 gaagattttg cagtttatta ctgtcagcac tatattaact ggcctctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 1290 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1290 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Ile Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 1291 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1291 cagagtgtta gcagcaac 18 <210> 1292 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1292 Gln Ser Val Ser Ser Asn 1 5 <210> 1293 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1293 ggtgcatcc 9 <210> 1294 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1294 Gly Ala Ser One <210> 1295 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1295 cagcactata ttaactggcc tctcact 27 <210> 1296 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1296 Gln His Tyr Ile Asn Trp Pro Leu Thr 1 5 <210> 1297 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1297 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgctg cgtctggatt taccttcaga agttatgcca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcaatg gtatactatg atggaaataa tcaatactat 180 gcagactccg tgaggggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agccgatgac acggctgtgt atttctgtgc gcgagggcct 300 gggtacaact ggctcgaccc ctggggccag ggaaccctgg tcaccgtctc ctca 354 <210> 1298 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1298 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Met Val Tyr Tyr Asp Gly Asn Asn Gln Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 1299 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1299 ggatttacct tcagaagtta tgcc 24 <210> 1300 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1300 Gly Phe Thr Phe Arg Ser Tyr Ala 1 5 <210> 1301 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1301 gtatactatg atggaaataa tcaa 24 <210> 1302 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1302 Val Tyr Tyr Asp Gly Asn Asn Gln 1 5 <210> 1303 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1303 gcgcgagggc ctgggtacaa ctggctcgac ccc 33 <210> 1304 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1304 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro 1 5 10 <210> 1305 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1305 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc aggaacttgg cctggtacca gcaaaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccggcc 180 aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctgcagtct 240 gaagattttg cagtttatta ctgtcagcag tataataact ggcctctcac tttcggcgga 300 gggaccaagg tggtgatcaa a 321 <210> 1306 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1306 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Val Ile Lys 100 105 <210> 1307 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1307 cagagtgtta gcaggaac 18 <210> 1308 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1308 Gln Ser Val Ser Arg Asn 1 5 <210> 1309 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1309 ggtgcatcc 9 <210> 1310 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1310 Gly Ala Ser One <210> 1311 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1311 cagcagtata ataactggcc tctcact 27 <210> 1312 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1312 Gln Gln Tyr Asn Asn Trp Pro Leu Thr 1 5 <210> 1313 <211> 354 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1313 caggtgcagt tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 gcctgtgttg cgtctggatt caccttcaga agttatggca tgcactgggt ccgccaggct 120 ccaggcaagg gactgcagtg ggtggcaatg atttactatg atggtaagaa taaatattat 180 gcagactccg tgaggggccg attcaccatc tccagagaca attccaagaa cacactgtat 240 ctgcaaatga acaatctgag agtcgaggac acggctatgt atttctgtgc gcgagggcct 300 gggtacaatt ggctcgaccc ctggggccag ggaaccctgg tcactgtttc ctca 354 <210> 1314 <211> 118 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1314 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ala Cys Val Ala Ser Gly Phe Thr Phe Arg Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Gln Trp Val 35 40 45 Ala Met Ile Tyr Tyr Asp Gly Lys Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Asn Leu Arg Val Glu Asp Thr Ala Met Tyr Phe Cys 85 90 95 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 1315 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1315 ggattcacct tcagaagtta tggc 24 <210> 1316 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1316 Gly Phe Thr Phe Arg Ser Tyr Gly 1 5 <210> 1317 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1317 atttactatg atggtaagaa taaa 24 <210> 1318 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1318 Ile Tyr Tyr Asp Gly Lys Asn Lys 1 5 <210> 1319 <211> 33 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1319 gcgcgagggc ctgggtacaa ttggctcgac ccc 33 <210> 1320 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1320 Ala Arg Gly Pro Gly Tyr Asn Trp Leu Asp Pro 1 5 10 <210> 1321 <211> 321 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1321 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagaattagc agcaacttgg cctggtacca gcaaaaacct 120 ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tagcccagcc 180 aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctgcagtct 240 gaggatgttg cagtttatta ctgtcagcaa catcataact ggcctctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 1322 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1322 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Arg Ile Ser Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ser Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Val Ala Val Tyr Cys Gln Gln His His Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 1323 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1323 cagagaatta gcagcaac 18 <210> 1324 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1324 Gln Arg Ile Ser Ser Asn 1 5 <210> 1325 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1325 ggtgcatcc 9 <210> 1326 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1326 Gly Ala Ser One <210> 1327 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1327 cagcaacatc ataactggcc tctcact 27 <210> 1328 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1328 Gln Gln His His Asn Trp Pro Leu Thr 1 5 <210> 1329 <211> 119 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1329 Asp Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Thr Thr Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <210> 1330 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1330 Gly Tyr Thr Phe Thr Arg Tyr Thr 1 5 <210> 1331 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1331 Ile Asn Pro Ser Arg Gly Tyr Thr 1 5 <210> 1332 <211> 12 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1332 Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr 1 5 10 <210> 1333 <211> 106 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1333 Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Tyr Met 20 25 30 Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Val Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Asn Ser Leu Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr 85 90 95 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 1334 <211> 11 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1334 Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Tyr 1 5 10 <210> 1335 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1335 Asp Thr Ser One <210> 1336 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1336 Gln Gln Trp Ser Ser Asn Pro Leu Thr 1 5 <210> 1337 <211> 367 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1337 gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt caccttttat gattatgcca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagctgga atagtgatac cataggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggccttat attactgtac aaaagatggc 300 agctatggtc acttctactc cggtttggac gtctggggcc aagggaccac ggtcaccgtc 360 tcctcag 367 <210> 1338 <211> 122 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1338 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Tyr Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Asp Thr Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Thr Lys Asp Gly Ser Tyr Gly His Phe Tyr Ser Gly Leu Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 1339 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1339 ggattcacct tttatgatta tgcc 24 <210> 1340 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1340 Gly Phe Thr Phe Tyr Asp Tyr Ala 1 5 <210> 1341 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1341 attagctgga atagtgatac cata 24 <210> 1342 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1342 Ile Ser Trp Asn Ser Asp Thr Ile 1 5 <210> 1343 <211> 45 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1343 acaaaagatg gcagctatgg tcacttctac tccggtttgg acgtc 45 <210> 1344 <211> 15 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1344 Thr Lys Asp Gly Ser Tyr Gly His Phe Tyr Ser Gly Leu Asp Val 1 5 10 15 <210> 1345 <211> 322 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1345 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca gcagaaacct 120 ggccaggctc cccgactcct catctatggt acatccacca gggccactgg tatcccagcc 180 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240 gaagattttg cagtttatta ctgtcaacaa tataataact ggccgctcac tttcggcgga 300 gggaccaagg tggagatcaa ac 322 <210> 1346 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1346 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Thr Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 1347 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1347 cagagtgtta gcagcaac 18 <210> 1348 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1348 Gln Ser Val Ser Ser Asn 1 5 <210> 1349 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1349 ggtacatcc 9 <210> 1350 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1350 Gly Thr Ser One <210> 1351 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1351 caacaatata ataactggcc gctcact 27 <210> 1352 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1352 Gln Gln Tyr Asn Asn Trp Pro Leu Thr 1 5 <210> 1353 <211> 379 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1353 gaagagcaac tggtggagtc tgggggagac ttggtacagc ctggcaggtc cctgaggctc 60 tcctgtgcag cctctggatt cacctttcat gattacacca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggaag tctaggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa gtccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggccttat attactgtgc aaaagatccc 300 tcttatggtt cggggtcgta tcactcctac tacggaatgg acgtctgggg ccaagggacc 360 acggtcactg tctcctcag 379 <210> 1354 <211> 126 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1354 Glu Glu Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe His Asp Tyr 20 25 30 Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Leu Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Pro Ser Tyr Gly Ser Gly Ser Tyr His Ser Tyr Tyr Gly 100 105 110 Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 1355 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1355 ggattcacct ttcatgatta cacc 24 <210> 1356 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1356 Gly Phe Thr Phe His Asp Tyr Thr 1 5 <210> 1357 <211> 24 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1357 attagttgga atagtggaag tcta 24 <210> 1358 <211> 8 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1358 Ile Ser Trp Asn Ser Gly Ser Leu 1 5 <210> 1359 <211> 57 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1359 gcaaaagatc cctcttatgg ttcggggtcg tatcactcct actacggaat ggacgtc 57 <210> 1360 <211> 19 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1360 Ala Lys Asp Pro Ser Tyr Gly Ser Gly Ser Tyr His Ser Tyr Tyr Gly 1 5 10 15 Met Asp Val <210> 1361 <211> 322 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1361 gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60 ctctcctgct gggccagtca gagtatagc aggtacttag tctggtacca acagaaatgt 120 ggccaggcac ccagactcct catctatgaa gcatctaaga gggccaccgg catcccagtc 180 aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagtct 240 gaagattttg cagtttatta ttgtcagcag cgtttcaatt ggcctctcac tttcggcgga 300 gggaccaagg tggagatcaa ac 322 <210> 1362 <211> 107 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1362 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Trp Ala Ser Gln Ser Ile Ser Arg Tyr 20 25 30 Leu Val Trp Tyr Gln Gln Lys Cys Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Glu Ala Ser Lys Arg Ala Thr Gly Ile Pro Val Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Phe Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 1363 <211> 18 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1363 cagagtatta gcaggtac 18 <210> 1364 <211> 6 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1364 Gln Ser Ile Ser Arg Tyr 1 5 <210> 1365 <211> 9 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1365 gaagcatct 9 <210> 1366 <211> 3 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1366 Glu Ala Ser One <210> 1367 <211> 27 <212> DNA <213> artificial sequence <220> <223> synthetic <400> 1367 cagcagcgtt tcaattggcc tctcact 27 <210> 1368 <211> 9 <212> PRT <213> artificial sequence <220> <223> synthetic <400> 1368 Gln Gln Arg Phe Asn Trp Pro Leu Thr 1 5 <210> 1369 <211> 297 <212> PRT <213> artificial sequence <220> <223> hCD20 <400> 1369 Met Thr Thr Pro Arg Asn Ser Val Asn Gly Thr Phe Pro Ala Glu Pro 1 5 10 15 Met Lys Gly Pro Ile Ala Met Gln Ser Gly Pro Lys Pro Leu Phe Arg 20 25 30 Arg Met Ser Ser Leu Val Gly Pro Thr Gln Ser Phe Phe Met Arg Glu 35 40 45 Ser Lys Thr Leu Gly Ala Val Gln Ile Met Asn Gly Leu Phe His Ile 50 55 60 Ala Leu Gly Gly Leu Leu Met Ile Pro Ala Gly Ile Tyr Ala Pro Ile 65 70 75 80 Cys Val Thr Val Trp Tyr Pro Leu Trp Gly Gly Ile Met Tyr Ile Ile 85 90 95 Ser Gly Ser Leu Leu Ala Ala Thr Glu Lys Asn Ser Arg Lys Cys Leu 100 105 110 Val Lys Gly Lys Met Ile Met Asn Ser Leu Ser Leu Phe Ala Ala Ile 115 120 125 Ser Gly Met Ile Leu Ser Ile Met Asp Ile Leu Asn Ile Lys Ile Ser 130 135 140 His Phe Leu Lys Met Glu Ser Leu Asn Phe Ile Arg Ala His Thr Pro 145 150 155 160 Tyr Ile Asn Ile Tyr Asn Cys Glu Pro Ala Asn Pro Ser Glu Lys Asn 165 170 175 Ser Pro Ser Thr Gln Tyr Cys Tyr Ser Ile Gln Ser Leu Phe Leu Gly 180 185 190 Ile Leu Ser Val Met Leu Ile Phe Ala Phe Phe Gln Glu Leu Val Ile 195 200 205 Ala Gly Ile Val Glu Asn Glu Trp Lys Arg Thr Cys Ser Arg Pro Lys 210 215 220 Ser Asn Ile Val Leu Leu Ser Ala Glu Glu Lys Lys Glu Gln Thr Ile 225 230 235 240 Glu Ile Lys Glu Glu Val Val Gly Leu Thr Glu Thr Ser Ser Gln Pro 245 250 255 Lys Asn Glu Glu Asp Ile Glu Ile Ile Pro Ile Gln Glu Glu Glu Glu 260 265 270 Glu Glu Thr Glu Thr Asn Phe Pro Glu Pro Pro Gln Asp Gln Glu Ser 275 280 285 Ser Pro Ile Glu Asn Asp Ser Ser Pro 290 295 <210> 1370 <211> 104 <212> PRT <213> artificial sequence <220> <223> hCD3 epsilon <400> 1370 Asp Gly Asn Glu Glu Met Gly Gly Ile Thr Gln Thr Pro Tyr Lys Val 1 5 10 15 Ser Ile Ser Gly Thr Thr Val Ile Leu Thr Cys Pro Gln Tyr Pro Gly 20 25 30 Ser Glu Ile Leu Trp Gln His Asn Asp Lys Asn Ile Gly Gly Asp Glu 35 40 45 Asp Asp Lys Asn Ile Gly Ser Asp Glu Asp His Leu Ser Leu Lys Glu 50 55 60 Phe Ser Glu Leu Glu Gln Ser Gly Tyr Tyr Val Cys Tyr Pro Arg Gly 65 70 75 80 Ser Lys Pro Glu Asp Ala Asn Phe Tyr Leu Tyr Leu Arg Ala Arg Val 85 90 95 Ser Glu Asn Ser Met Glu Met Asp 100 <210> 1371 <211> 79 <212> PRT <213> artificial sequence <220> <223> hCD3 delta <400> 1371 Phe Lys Ile Pro Ile Glu Glu Leu Glu Asp Arg Val Phe Val Asn Cys 1 5 10 15 Asn Thr Ser Ile Thr Trp Val Glu Gly Thr Val Gly Thr Leu Leu Ser 20 25 30 Asp Ile Thr Arg Leu Asp Leu Gly Lys Arg Ile Leu Asp Pro Arg Gly 35 40 45 Ile Tyr Arg Cys Asn Gly Thr Asp Ile Tyr Lys Asp Lys Glu Ser Thr 50 55 60 Val Gln Val His Tyr Arg Met Ser Gln Ser Ser Val Glu Leu Asp 65 70 75 <210> 1372 <211> 227 <212> PRT <213> artificial sequence <220> <223> hFc-delta-Adp <400> 1372 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <210> 1373 <211> 227 <212> PRT <213> artificial sequence <220> <223> hFc <400> 1373 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <210> 1374 <211> 233 <212> PRT <213> artificial sequence <220> <223> mFc-delta-Adp <400> 1374 Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro 1 5 10 15 Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys 20 25 30 Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val 35 40 45 Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe 50 55 60 Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu 65 70 75 80 Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His 85 90 95 Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys 100 105 110 Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser 115 120 125 Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met 130 135 140 Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro 145 150 155 160 Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn 165 170 175 Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met 180 185 190 Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser 195 200 205 Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn Arg Phe Thr Thr 210 215 220 Lys Ser Phe Ser Arg Thr Pro Gly Lys 225 230 <210> 1375 <211> 233 <212> PRT <213> artificial sequence <220> <223> mFc <400> 1375 Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro 1 5 10 15 Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys 20 25 30 Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val 35 40 45 Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe 50 55 60 Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu 65 70 75 80 Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His 85 90 95 Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys 100 105 110 Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser 115 120 125 Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met 130 135 140 Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro 145 150 155 160 Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn 165 170 175 Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met 180 185 190 Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser 195 200 205 Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr 210 215 220 Lys Ser Phe Ser Arg Thr Pro Gly Lys 225 230

Claims (24)

An isolated human antibody or antigen-binding fragment thereof that binds human CD3 with an association dissociation equilibrium constant (K _D ) of less than 2 nM as measured by a surface plasmon resonance assay at 25° C. in an antigen-capture format, wherein the antibody or antigen -An isolated human antibody or antigen thereof, wherein the binding fragment comprises six complementarity determining regions (HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) each comprising an amino acid sequence selected from the group consisting of the following SEQ ID NOs- Combined Fragments:
SEQ ID NOs: 4-6-8-12-14-16, 20-22-24-28-30-32, 36-38-40-44-46-48, 52-54-56-60-62-64, 68-70-72-76-78-80, 84-86-88-92-94-96, 100-102-104-108-110-112, 116-118-120-124-126-128, 132- 134-136-140-142-144, 148-150-152-156-158-160, 164-166-168-172-174-176, 180-182-184-188-190-192, 196-198- 200-204-206-208, 212-214-216-220-222-224, 244-246-248-252-254-256, 260-262-264-268-270-272, 276-278-280- 284-286-288, 292-294-296-300-302-304, 308-310-312-316-318-320, 324-326-328-332-334-336, 340-342-344-348- 350-352, 356-358-360-364-366-368, 388-390-392-396-398-400, 404-406-408-412-414-416, 420-422-424-428-430- 432; 436-438-440-444-446-448; 468-470-472-476-478-480; 484-486-488-492-494-496; 596-598-600-604-606-608, 612-614-616-620-622-624, 628-630-632-636-638-640, 724-726-728-732-734-736, 772- 774-776-780-782-784, 788-790-792-796-798-800, 804-806-808-812-814-816, 852-854-856-860-862-864, 884-886- 888-892-894-896, 900-902-904-908-910-912, 932-934-936-940-942-944, 948-950-952-956-958-960, 1044-1046 -1048-1236-1238-1240, 1052-1054-1056-1236-1238-1240, 1068-1070-1072-1236-1238-1240, 1076-1078-1080-1236-1238-1240, 1100-11402-1102 -1236-1238-1240, 1108-1110-1112-1236-1238-1240, 1116-1118-1120-1236-1238-1240, 1124-1126-1128-1236-1238-1240, 1140-1142-1144-12 -1238-1240, 1148-1150-1152-1236-1238-1240, 1164-1166-1168-1236-1238-1240, and 1180-1182-1184-1236-1238-1240. 2. The method of claim 1, wherein the antibody or antigen-binding fragment thereof comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 comprising each of the amino acid sequences of SEQ ID NOs: 116-118-120-124-126-128. An isolated antibody or antigen-binding fragment. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof binds to human CD3 with a K _D of less than 500 pM as measured by surface plasmon resonance assay at 25° C. in an antigen-capture format, and the antibody or antigen-binding fragment thereof binds to human CD3. An isolated antibody or antigen-binding fragment, wherein the binding fragment comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 each comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:
SEQ ID NOs: 20-22-24-28-30-32, 36-38-40-44-46-48, 84-86-88-92-94-96, 100-102-104-108-110-112, 116-118-120-124-126-128, 132-134-136-140-142-144, 148-150-152-156-158-160, 164-166-168-172-174-176, 212- 214-216-220-222-224, 244-246-248-252-254-256, 260-262-264-268-270-272, 276-278-280-284-286-288, 292-294- 296-300-302-304, 308-310-312-316-318-320, 340-342-344-348-350-352, 356-358-360-364-366-368, 404-406-408- 412-414-416, 420-422-424-428-430-432, 436-438-440-444-446-448, 484-486-488-492-494-496, 516-518-520-524- 526-528, 724-726-728-732-734-736, 772-774-776-780-782-784, 788-790-792-796-798-800, 852-854-856-860-862- 864; 884-886-888-892-894-896; 900-902-904-908-910-912; 932-934-936-940-942-944; 1044-1046-1048-1236-1238-1240; 1052-1054-1056-1236-1238-1240; 1068-1070-1072-1236-1238-1240; -1102-1104-1236-1238-1240. 4. The method of claim 3, wherein the antibody or antigen-binding fragment thereof binds to human CD3 with a K _D of less than 100 pM as measured by a surface plasmon resonance assay at 25° C. in an antigen-capture format, and the antibody or antigen-binding fragment thereof binds to human CD3. An isolated antibody or antigen-binding fragment comprising HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 wherein the fragment each comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:
SEQ ID NOs: 100-102-104-108-110-112, 116-118-120-124-126-128, 340-342-344-348-350-352, 356-358-360-364-366-368, 420-422-424-428-430-432, 516-518-520-524-526-528, and 772-774-776-780-782-784. 2. The isolated antibody or antigen-binding fragment thereof of claim 1, which binds human CD3 with a dissociation half-life (t1/2) of greater than 10 minutes as measured by a surface plasmon resonance assay at 25°C in an antigen-capture format. , wherein the antibody or antigen-binding fragment comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 each comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:
SEQ ID NOs: 4-6-8-12-14-16, 20-22-24-28-30-32, 36-38-40-44-46-48, 52-54-56-60-62-64, 68-70-72-76-78-80, 84-86-88-92-94-96, 100-102-104-108-110-112, 116-118-120-124-126-128, 132- 134-136-140-142-144, 148-150-152-156-158-160, 164-166-168-172-174-176, 180-182-184-188-190-192, 196-198- 200-204-206-208, 212-214-216-220-222-224, 244-246-248-252-254-256, 260-262-264-268-270-272, 276-278-280- 284-286-288, 292-294-296-300-302-304, 308-310-312-316-318-320, 324-326-328-332-334-336, 340-342-344-348- 350-352, 356-358-360-364-366-368, 388-390-392-396-398-400, 404-406-408-412-414-416, 420-422-424-428-430- 432; 436-438-440-444-446-448; 468-470-472-476-478-480; 484-486-488-492-494-496; 596-598-600-604-606-608, 612-614-616-620-622-624, 628-630-632-636-638-640, 724-726-728-732-734-736, 772- 774-776-780-782-784, 788-790-792-796-798-800, 804-806-808-812-814-816, 852-854-856-860-862-864, 884-886- 888-892-894-896, 900-902-904-908-910-912, 932-934-936-940-942-944, 948-950-952-956-958-960, 1044-1046 -1048-1236-1238-1240, 1052-1054-1056-1236-1238-1240, 1068-1070-1072-1236-1238-1240, 1076-1078-1080-1236-1238-1240, 1100-11402-1102 -1236-1238-1240, 1108-1110-1112-1236-1238-1240, 1116-1118-1120-1236-1238-1240, 1124-1126-1128-1236-1238-1240, 1140-1142-1144-12 -1238-1240, 1148-1150-1152-1236-1238-1240, 1164-1166-1168-1236-1238-1240, and 1180-1182-1184-1236-1238-1240. 6. The method of claim 5, wherein the antibody or antigen-binding fragment thereof binds to human CD3 with a t1/2 of greater than 100 minutes as measured by a surface plasmon resonance assay at 25°C in an antigen-capture format, and the antibody or antigen -An isolated antibody or antigen-binding fragment, wherein the binding fragment comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 each comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:
SEQ ID NOs: 4-6-8-12-14-16, 20-22-24-28-30-32, 52-54-56-60-62-64, 84-86-88-92-94-96, 100-102-104-108-110-112, 116-118-120-124-126-128, 132-134-136-140-142-144, 340-342-344-348-350-352, 356- 358-360-364-366-368, 468-470-472-476-478-480, 484-486-488-492-494-496, 516-518-520-524-526-528, 612-614- 616-620-622-624, 772-774-776-780-782-784, 1044-1046-1048-1236-1238-1240, 1052-1054-1056-1236-1238-1240, 1068-1070-1072- 1236-1238-1240, and 1100-1102-1104-1236-1238-1240. The method of claim 1, wherein the antibody or antigen-binding fragment is SEQ ID NO: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/122, 130/ 138, 146/154, 162/170, 178/186, 194/202, 210/218, 242/250, 258/266, 274/282, 290/298, 306/314, 322/330, 338/346, 354/362, 386/394, 402/410, 418/426, 434/442, 466/474, 482/490, 514/522, 594/602, 610/618, 626/634, 722/730, 770/ 778, 786/794, 802/810, 850/858, 882/890, 898/906, 930/938, 946/954, 1042/1234, 1050/1234, 1066/1234, 1074/1234, 1098/1234, Heavy chain variable region (HCVR)/light chain variable region (LCVR) amino acid sequence pairs selected from the group consisting of 1106/1234, 1114/1234, 1122/1234, 1138/1234, 1146/1234, 1162/1234, and 1178/1234 An isolated antibody or antigen-binding fragment comprising a. 8. The antibody of claim 7, wherein the antibody or antigen-binding fragment comprises an HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 2/10, 114/122, 162/170 and 178/186. or an antigen-binding fragment. 9. The isolated antibody or antigen-binding fragment of claim 8, wherein the antibody or antigen-binding fragment comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 114 and an LCVR comprising the amino acid sequence of SEQ ID NO: 122. The method of claim 1, wherein the antibody or antigen-binding fragment induces human T-cell proliferation and monkey T-cell proliferation in vitro, and the antibody or antigen-binding fragment is each selected from the group consisting of the following SEQ ID NOs: An isolated antibody or antigen-binding fragment comprising the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 comprising the amino acid sequence:
SEQ ID NOs: 4-6-8-12-14-16, 116-118-120-124-126-128, 724-726-728-732-734-736, 772-774-776-780-782-784, 788-790-792-796-798-800, 804-806-808-812-814-816, 1044-1046-1048-1236-1238-1240, 1052-1054-1056-1236-1238-1240, 1068- 1070-1072-1236-1238-1240, 1076-1078-1080-1236-1238-1240, 1100-1102-1104-1236-1238-1240, 1108-1110-1112-1236-1238-1240, 1116-1116 1120-1236-1238-1240; 1124-1126-1128-1236-1238-1240; 1140-1142-1144-1236-1238-1240; 1148-1150-1152-1236-1238-1240; 1236-1238-1240, and 1180-1182-1184-1236-1238-1240. 11. The method of claim 10, wherein the antibody or antigen-binding fragment is SEQ ID NO: 2/10, 114/122, 722/730, 770/778, 786/794, 802/810, 1042/1234, 1050/1234, 1066/ HCVR/LCVR amino acid sequence pairs selected from the group consisting of 1234, 1074/1234, 1098/1234, 1106/1234, 1114/1234, 1122/1234, 1138/1234, 1146/1234, 1162/1234, and 1178/1234 An isolated antibody or antigen-binding fragment comprising a. 12. The isolated antibody or antigen-binding fragment of any one of claims 1 to 11, which is an antibody comprising a human IgG1 heavy chain constant region. 12. The isolated antibody or antigen-binding fragment of any one of claims 1 to 11, which is an antibody comprising a human IgG4 heavy chain constant region. 12. The isolated antibody or antigen-binding fragment of any one of claims 1 to 11, which is a bispecific antibody or antigen-binding fragment thereof. A pharmaceutical composition for treating a tumor in a subject in need thereof, comprising the antibody or antigen-binding fragment of any one of claims 1 to 11 and a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition for treating a tumor in a subject in need thereof, comprising the bispecific antibody or antigen-binding fragment of claim 14 . 17. The pharmaceutical composition of claim 16, wherein the tumor is a B-cell cancer. 18. The method of claim 17, wherein the B-cell cancer is follicular lymphoma, B cell chronic lymphocytic leukemia, B cell lymphoblastic lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse large B cell lymphoma, A pharmaceutical composition selected from the group consisting of marginal zone lymphoma, mantle cell lymphoma, hairy cell leukemia and Burkitt's lymphoma. 19. The pharmaceutical composition of claim 18, wherein the B-cell cancer is follicular lymphoma. 19. The pharmaceutical composition of claim 18, wherein the B-cell cancer is diffuse large B-cell lymphoma. 19. The pharmaceutical composition of claim 18, wherein the B-cell cancer is marginal zone lymphoma. 19. The pharmaceutical composition of claim 18, wherein the B-cell cancer is mantle cell lymphoma. delete delete

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